Dosage form compositions comprising an inhibitor of bruton&#39;s tyrosine kinase

ABSTRACT

The invention relates generally crystalline mesylate salts, crystalline chloride salts and crystalline sulfate salts of the compound (S)-2-(3′-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4′-bipyridin]-2′-yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one that is an inhibitor of Bruton&#39;s tyrosine kinase. In some aspects, the crystalline salts are single polymorphs.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.16/889,308, filed Jun. 1, 2020, which is a divisional of U.S.application Ser. No. 16/272,510, filed Feb. 11, 2019, which is adivisional of U.S. application Ser. No. 15/442,774, filed Feb. 27, 2017,issued as U.S. Pat. No. 10,246,461 on Apr. 2, 2019, which claimspriority to U.S. Provisional Application No. 62/301,373 filed Feb. 29,2016, the disclosure of each of which is incorporated herein in itsentirety.

FIELD OF THE DISCLOSURE

The field of the disclosure relates generally to pharmaceutical dosageform compositions comprising compounds which inhibit Bruton's TyrosineKinase (Btk) activity which are useful for treating disorders mediatedby Btk including inflammation, immunological diseases, and cancer.

BACKGROUND

Protein kinases, the largest family of human enzymes, encompass wellover 500 proteins. Bruton's Tyrosine Kinase (Btk) is a member of the Tecfamily of tyrosine kinases, and is a regulator of early B-celldevelopment as well as mature B-cell activation, signaling, andsurvival.

B-cell signaling through the B-cell receptor (BCR) can lead to a widerange of biological outputs, which in turn depend on the developmentalstage of the B-cell. The magnitude and duration of BCR signals must beprecisely regulated. Aberrant BCR-mediated signaling can causedisregulated B-cell activation and/or the formation of pathogenicauto-antibodies leading to multiple autoimmune and/or inflammatorydiseases. Mutation of Btk in humans results in X-linkedagammaglobulinaemia (XLA). This disease is associated with the impairedmaturation of B-cells, diminished immunoglobulin production, compromisedT-cell-independent immune responses and marked attenuation of thesustained calcium sign upon BCR stimulation. Evidence for the role ofBtk in allergic disorders and/or autoimmune disease and/or inflammatorydisease has been established in Btk-deficient mouse models. For example,in standard murine preclinical models of systemic lupus erythematosus(SLE), Btk deficiency has been shown to result in a marked ameliorationof disease progression. Moreover, Btk deficient mice can also beresistant to developing collagen-induced arthritis and can be lesssusceptible to Staphylococcus-induced arthritis. A large body ofevidence supports the role of B-cells and the humoral immune system inthe pathogenesis of autoimmune and/or inflammatory diseases.Protein-based therapeutics (such as Rituxan) developed to depleteB-cells, represent an approach to the treatment of a number ofautoimmune and/or inflammatory diseases. Because of Btk's role in B-cellactivation, inhibitors of Btk can be useful as inhibitors of B-cellmediated pathogenic activity (such as autoantibody production). Btk isalso expressed in osteoclasts, mast cells and monocytes and has beenshown to be important for the function of these cells. For example, Btkdeficiency in mice is associated with impaired IgE-mediated mast cellactivation (marked diminution of TNF-alpha and other inflammatorycytokine release), and Btk deficiency in humans is associated withgreatly reduced TNF-alpha production by activated monocytes.

Thus, inhibition of Btk activity can be useful for the treatment ofallergic disorders and/or autoimmune and/or inflammatory diseases suchas: SLE, rheumatoid arthritis, multiple vasculitides, idiopathicthrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis,and asthma (Di Paolo et al (2011) Nature Chem. Biol. 7(1):41-50; Liu etal (2011) Jour. of Pharm. and Exper. Ther. 338(1):154-163). In addition,Btk has been reported to play a role in apoptosis; thus, inhibition ofBtk activity can be useful for cancer, as well as the treatment ofB-cell lymphoma, leukemia, and other hematological malignancies.Moreover, given the role of Btk in osteoclast function, the inhibitionof Btk activity can be useful for the treatment of bone disorders suchas osteoporosis. Specific Btk inhibitors have been reported (Liu (2011)Drug Metab. and Disposition 39(10):1840-1849; U.S. Pat. No. 7,884,108,WO 2010/056875; U.S. Pat. Nos. 7,405,295; 7,393,848; WO 2006/053121;U.S. Pat. No. 7,947,835; US 2008/0139557; U.S. Pat. No. 7,838,523; US2008/0125417; US 2011/0118233; PCT/US2011/050034“PYRIDINONES/PYRAZINONES, METHOD OF MAKING, AND METHOD OF USE THEREOF”,filed 31 Aug. 2011; PCT/US2011/050013 “PYRIDAZINONES, METHOD OF MAKING,AND METHOD OF USE THEREOF”, filed 31 Aug. 2011; U.S. Ser. No. 13/102,720“PYRIDONE AND AZA-PYRIDONE COMPOUNDS AND METHODS OF USE”, filed 6 May2011).

U.S. Pat. No. 8,716,274 (incorporated by reference herein in itsentirety) discloses classes of heteroaryl pyridine and aza-pyridonecompounds useful for inhibiting Btk. Compound (A) depicted below is oneparticular Btk inhibitor compound, where the asterisk refers to a chiralcenter:

The S enantiomer of compound (A) is:(S)-2-(3′-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4′-bipyridin]-2′-yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one.The R enantiomer of compound (A) is:(R)-2-(3′-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4′-bipyridin]-2′-yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one.

Compound (A) is a weak base exhibiting a pH-dependent solubility profilehaving an aqueous solubility of about 6.5 mg/mL at pH 2.6 and asolubility of about 0.001 mg/mL at pH 5.0. Many patients that couldbenefit from treatment with Btk inhibitors take a stomach acid reducingagent (“ARA”) such as a proton pump inhibitor (“PPI”) for the treatmentof gastric reflux disease. Problematically, such patients may beachlorhydric and exhibit a stomach pH of from about 4 to about 6 therebyreducing the solubility and concomitant bioavailability of weak base Bktinhibitors such as compound (A). Thus there may be decreased drugexposure in patients taking ARAs.

A need therefore exists for compositions that mitigate pH-dependentsolubility risks associated with compound (A) and that provide forimproved bioavailability in patients exhibiting achlorohydria.

BRIEF DESCRIPTION

In some aspects, tablet compositions are provided. The tablets comprisefrom about 25 mg to about 300 mg of a free base of structure (I)

and from about 5 wt. % to about 50 wt. % fumaric acid.

In some aspects, salt compositions are provided. The salt compositionscomprise a cation formed from a free base of structure (I) recited aboveand an anion, such as an anion selected from mesylate, chloride andsulfate.

In some aspects, amorphous solid dispersion compositions are provided.The compositions comprise a polymeric component and from about 20 wt. %to about 60 wt. % of a free base of structure (I) recited above.

In some other aspects, pharmaceutical compositions comprising: (i) thecombination of from about 25 mg to about 300 mg of a free base ofstructure (I) and from about 5 wt. % to about 50 wt. % fumaric acid,(ii) salt compositions comprising a cation formed from a free base ofstructure (I) and an anion selected from mesylate, chloride and sulfate,or (iii) amorphous solid dispersions comprising a polymeric componentand from about 20 wt. % to about 60 wt. % of a free base of structure(I) are provided.

In other aspects, a method of treating a condition selected from immunedisorders, cancer, cardiovascular disease, viral infection,inflammation, metabolism/endocrine function disorders and neurologicaldisorders in an achlorhydric patient is provided. The method comprisesadministering a pharmaceutical composition as previously described to apatient in need of such treatment.

In other aspects, a kit for treating a condition selected from immunedisorders, cancer, cardiovascular disease, viral infection,inflammation, metabolism/endocrine function disorders and neurologicaldisorders in an achlorhydric patient is provided. The kit comprises: (1)a pharmaceutical composition as previously described; and (2)instructions for use.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides an overlay of powder X-ray diffraction (XRPD) patternsof compound (I) free base Type A crystals used in some of the examplesherein and compound (I) free base Type A crystal standard.

FIG. 2 provides a thermogravimetric analysis (TGA) graph and adifferential scanning calorimetric (DSC) graph for compound (I) freebase Type A crystals.

FIG. 3A provides an overlay of XRPD patterns of compound (I) mesylatesalt Type A crystals prepared according to an aspect of the presentdisclosure as compared to standard compound (I) mesylate salt Type Acrystals. FIG. 3B provides an XRPD pattern of compound (I) mesylate saltType A crystals prepared according to an aspect of the presentdisclosure.

FIG. 4 provides a dynamic vapor sorption (DVS) graph of compound (I)mesylate salt type A.

FIG. 5 provides a XPRD graph of compound (I) mesylate type A salt beforeand after DVS.

FIG. 6 provides an overlay of XRPD patterns of compound (I) mesylatesalt Type A crystals prepared according to an aspect of the presentdisclosure as compared to standard compound (I) mesylate salt Type Acrystals.

FIG. 7 provides a TGA graph and a DSC graph for compound (I) mesylatesalt Type A crystals.

FIG. 8 provides a 1H NMR graph of compound (I) mesylate salt Type Acrystals.

FIG. 9 provides a graph of in vitro compound (I) free base dissolutionrate in a simulated achlorohydric stomach medium (pH 4.5, 0-30 min) andin a simulated intestinal medium (pH 6.5, 30-240 min) when combined witheach of fumaric acid, succinic acid and citric acid.

FIG. 10 provides a graph of in vitro compound (I) free base dissolutionrate in a simulated achlorohydric stomach medium (pH 4.5, 0-30 min) andin a simulated intestinal medium (pH 6.5, 30-240 min) in the absence offumaric acid and in combination with various concentrations of fumaricacid.

FIG. 11 provides a graph of in vitro dissolution rates of tabletscomprising compound (I) free base not containing fumaric acid and intablets comprising compound (I) free base in combination with varyingamounts of fumaric acid in a simulated achlorohydric stomach medium (pH4.5, 0-30 min) and in a simulated intestinal medium (pH 6.5, 30-240min).

FIG. 12 provides a graph of in vitro dissolution of amorphous soliddispersions prepared from compound (I) free base and a polymer in asimulated normal stomach medium (pH of 1) and in a simulated intestinalmedium.

FIG. 13 provides a graph of in vitro dissolution of amorphous soliddispersions prepared from compound (I) free base and a polymer of FIG.12 in a simulated achlorohydric stomach medium (pH of 4) and in asimulated intestinal medium.

FIG. 14 provides a graph of in vitro dissolution of amorphous soliddispersions prepared from compound (I) free base and a polymer of FIG.12 in a simulated achlorohydric stomach medium (pH of 5) and in asimulated intestinal medium.

FIG. 15A provides a graph of in vitro dissolution of amorphous soliddispersions prepared from compound (I) free base and a polymer in asimulated normal stomach medium (pH of 1) and in a simulated intestinalmedium. FIG. 15B zooms in on the concentration range for the simulatedintestinal phase of the experiment.

FIG. 16A provides a graph of in vitro dissolution of amorphous soliddispersions prepared from compound (I) free base and a polymer in asimulated achlorohydric stomach medium (pH of 4.5) and in a simulatedintestinal medium. FIG. 16B zooms in on the concentration range for thesimulated intestinal phase of the experiment.

FIG. 17 provides a first graph of plasma concentration versus time fortablets comprising compound (I) free base and fumaric acid in a caninepharmacokinetics study.

FIG. 18 provides a second graph of plasma concentration versus time fortablets comprising compound (I) free base and fumaric acid in a caninepharmacokinetics study.

FIG. 19A provides a graph of human in vivo plasma Cmax (ng/mL) for a 200mg tableted dose of compound (I) free base in combination with fumaricacid in a 1:1 wt. % ratio under fasted conditions, under fed conditions,and under fed conditions wherein the subject was administered 20 mgRabeprazole (PPI) twice per day (BID). FIG. 19B provides a graph ofhuman in vivo plasma AUCinf (hr*ng/mL) for a 200 mg tableted dose ofcompound (I) free base in combination with fumaric acid in a 1:1 wt. %ratio under fasted conditions, under fed conditions, and under fedconditions wherein the subject was administered 20 mg Rabeprazole (PPI)twice per day (BID).

FIG. 20A provides a graph of human in vivo plasma Cmax (ng/mL) for: (i)a 200 mg powder-in-capsule dose of compound (I) free base in the absenceof excipients and in the absence of fumaric acid, (ii) a 200 mg tableteddose of compound (I) free base comprising a 1:1 weight ratio of fumaricacid, and (iii) and a 200 mg tableted dose of compound (I) free basecomprising at 1:1 weight ratio of fumaric acid, wherein the subject wasadministered 20 mg Rabeprazole (PPI) twice per day (BID). FIG. 20Bprovides a graph of human in vivo plasma AUCinf (hr*ng/mL) for: (i) a200 mg powder-in-capsule dose of compound (I) free base in the absenceof excipients and in the absence of fumaric acid, (ii) a 200 mg tableteddose of compound (I) free base comprising a 1:1 weight ratio of fumaricacid, and (iii) and a 200 mg tableted dose of compound (I) free basecomprising at 1:1 weight ratio of fumaric acid, wherein the subject wasadministered 20 mg Rabeprazole (PPI) twice per day (BID).

FIG. 21A provides a graph of human in vivo plasma concentration (ng/mL)versus time for a dose of a powder-in-capsule containing 100 mg compound(I) free base in the absence of excipients and in the absence of fumaricacid under (i) fasted conditions, (ii) fed conditions, (iii) fastedconditions wherein the subject was administered 20 mg Rabeprazole (PPI)twice per day (BID) for three days prior to, and on the day of, compound(I) dosing, and (iv) fed conditions wherein the subject was administered20 mg Rabeprazole (PPI) twice per day (BID) for three days prior to, andon the day of, compound (I) dosing. FIG. 21B provides a graph of humanin vivo plasma concentration (ng/mL, logarithmic scale) versus time fora dose of powder-in-capsule containing 100 mg compound (I) free base inthe absence of excipients and in the absence of fumaric acid underfasted conditions, under fed conditions, and under (i) fastedconditions, (ii) fed conditions, (iii) fasted conditions wherein thesubject was administered 20 mg Rabeprazole (PPI) twice per day (BID) forthree days prior to, and on the day of, compound (I) dosing, and (iv)fed conditions wherein the subject was administered 20 mg Rabeprazole(PPI) twice per day (BID) for three days prior to, and on the day of,compound (I) dosing.

FIG. 22A provides a graph of human in vivo plasma concentration (ng/mL)versus time for a dose of a powder-in-capsule containing 100 mg compound(I) free base in the absence of excipients and in the absence of fumaricacid under fasted conditions. FIG. 22B provides a graph of human in vivoplasma concentration (ng/mL, logarithmic scale) versus time for a doseof a powder-in-capsule containing 100 mg compound (I) free base in theabsence of excipients and in the absence of fumaric acid under fastedconditions.

FIG. 23A provides a graph of human in vivo plasma concentration (ng/mL)versus time for a dose of a powder-in-capsule containing 100 mg compound(I) free base in the absence of excipients and in the absence of fumaricacid under fed conditions. FIG. 23B provides a graph of human in vivoplasma concentration (ng/mL, logarithmic scale) versus time for a doseof a powder-in-capsule containing 100 mg compound (I) free base in theabsence of excipients and in the absence of fumaric acid under fedconditions.

FIG. 24A provides a graph of human in vivo plasma concentration (ng/mL)versus time for a dose of a powder-in-capsule containing 100 mg compound(I) free base in the absence of excipients and in the absence of fumaricacid under fasted conditions wherein the subject was administered 20 mgRabeprazole (PPI) twice per day (BID) for three days prior to, and onthe day of, compound (I) dosing. FIG. 24B provides a graph of human invivo plasma concentration (ng/mL, logarithmic scale) versus time for adose of a powder-in-capsule containing 100 mg compound (I) free base inthe absence of excipients and in the absence of fumaric acid underfasted conditions wherein the subject was administered 20 mg Rabeprazole(PPI) twice per day (BID) for three days prior to, and on the day of,compound (I) dosing.

FIG. 25A provides a graph of human in vivo plasma concentration (ng/mL)versus time for a dose of a powder-in-capsule containing 100 mg compound(I) free base in the absence of excipients and in the absence of fumaricacid under fed conditions wherein the subject was administered 20 mgRabeprazole (PPI) twice per day (BID) for three days prior to, and onthe day of, compound (I) dosing. FIG. 25B provides a graph of human invivo plasma concentration (ng/mL, logarithmic scale) versus time for adose of a powder-in-capsule containing 100 mg compound (I) free base inthe absence of excipients and in the absence of fumaric acid under fedconditions wherein the subject was administered 20 mg Rabeprazole (PPI)twice per day (BID) for three days prior to, and on the day of, compound(I) dosing.

FIG. 26A provides a graph of human in vivo plasma Cmax (ng/mL) for adose of a powder-in-capsule containing 100 mg compound (I) free base inthe absence of excipients and in the absence of fumaric acid under (i)fasted conditions, (ii) fed conditions, (iii) fasted conditions whereinthe subject was administered 20 mg Rabeprazole (PPI) twice per day (BID)for three days prior to, and on the day of, compound (I) dosing, and(iv) fed conditions wherein the subject was administered 20 mgRabeprazole (PPI) twice per day (BID) for three days prior to, and onthe day of, compound (I) dosing. FIG. 26B provides a graph of human invivo plasma AUCinf (hr*ng/mL) for a dose of a powder-in-capsulecontaining 100 mg compound (I) free base in the absence of excipientsand in the absence of fumaric acid under (i) fasted conditions, (ii) fedconditions, (iii) fasted conditions wherein the subject was administered20 mg Rabeprazole (PPI) twice per day (BID) for three days prior to, andon the day of, compound (I) dosing, and (iv) fed conditions wherein thesubject was administered 20 mg Rabeprazole (PPI) twice per day (BID) forthree days prior to, and on the day of, compound (I) dosing.

FIG. 27 provides an overlay of XRPD patterns of compound (I) chlorideType A crystals and compound (I) amorphous chloride salt.

FIG. 28 provides an overlay of powder XRPD patterns of compound (I)chloride Type A crystals (i) prepared at 100 mg scale in according to afirst aspect of the disclosure and (ii) prepared at 500 mg scale inaccording to a second aspect of the disclosure as compared to compound(I) chloride Type A crystal standard.

FIG. 29 provides an overlay of powder XRPD patterns of compound (I)chloride salt Type A crystals prepared according to a third aspect ofthe disclosure as compared to compound (I) chloride salt Type A crystalstandard.

FIG. 30 provides and XRPD pattern of compound (I) sulfate salt Type Acrystals prepared according to an aspect of the disclosure.

FIG. 31 provides an overlay of powder XRPD patterns of compound (I)sulfate salt Type A crystals prepared from compound (I) free base andsulfuric acid at mole ratios of free base to acid of 0.49:1 and 0.81:1as compared to compound (I) free base.

DETAILED DESCRIPTION

Reference will now be made in detail to certain aspects of thedisclosure, examples of which are illustrated in the accompanyingstructures and formulas. While the disclosure will be described inconjunction with the enumerated aspects, it will be understood that theyare not intended to limit the invention to those aspects. On thecontrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application, including but not limited to defined terms, termusage, described techniques, or the like, this application controls.Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the invention, suitable methods and materials aredescribed below. All publications, patent applications, patents, andother references mentioned herein are incorporated by reference in theirentirety. The nomenclature used in this Application is based on IUPACsystematic nomenclature, unless indicated otherwise.

The disclosure is directed to pharmaceutical compositions comprising theS-enantiomer of compound (A):(S)-2-(3′-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4′-bipyridin]-2′-yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one,depicted below as compound (I), in the form of a free base or a salt.

Some aspects of the disclosure relate to tablet compositions comprisingcompound (I) free base in combination with fumaric acid. Some otheraspects of the disclosure relate to salt compositions comprising acation formed from compound (I) free base. Some further aspects of thedisclosure relate to amorphous solid dispersions comprising compound (I)free base and a polymeric component. Each of the various compositions ofthe disclosure provide for improved dissolution of compound (I) at a pHof from about 4 to about 6 as compared to compound (I) free base alone.

Definitions

As used herein “achlorohydria” and “achlorohydric” refer to states wherethe production of hydrochloric acid in gastric secretions of the stomachand other digestive organs is low or absent. A typical stomach pHassociated with achlorohydria is from about 4 to about 6. In someaspects of the disclosure, achlorohydria may result from the use ofantacids or drugs that decrease gastric acid production (such asH2-receptor antagonists) or transport (such as proton pump inhibitors(“PPI”)).

As used herein, the term “amorphous” or “amorphous form” is intended tomean that the substance, component, or product in question is notessentially crystalline as determined, for instance, by XRPD or wherethe substance, component, or product in question, for example is notbirefringent when viewed microscopically. In certain aspects, a samplecomprising an amorphous form of a substance may be essentially free ofother amorphous forms and/or crystalline forms.

As used herein, the term “amorphous solid dispersion” (“ASD”) refer tocompositions having an amorphous active ingredient essentially dispersedin a polymer or mixture of polymers.

As used herein “essentially” refers to at least 80%, at least 85%, atleast 90%, at least 95% or at least 99% on a specified basis.

As used herein, the terms “crystalline” and “crystal” refer to acrystalline solid form of a chemical compound, including, but notlimited to, a single-component or multiple-component crystal form, e.g.,a polymorph of a compound; or a solvate, a hydrate, a clathrate, aco-crystal, a salt of a compound, or a polymorph thereof. The term“crystal forms” and related terms herein refers to the variouscrystalline modifications of a given substance, including, but notlimited to, polymorphs, solvates, hydrates, co-crystals and othermolecular complexes, as well as salts, solvates of salts, hydrates ofsalts, other molecular complexes of salts, and polymorphs thereof.Crystal forms of a substance can be obtained by a number of methods, asknown in the art. Such methods include, but are not limited to, meltrecrystallization, melt cooling, solvent recrystallization,recrystallization in confined spaces such as, e.g., in nanopores orcapillaries, recrystallization on surfaces or templates such as, e.g.,on polymers, recrystallization in the presence of additives, such as,e.g., co-crystal counter-molecules, desolvation, dehydration, rapidevaporation, rapid cooling, slow cooling, vapor diffusion, sublimation,grinding and solvent-drop grinding.

Techniques for characterizing crystal forms and amorphous forms areknown in the art and include, but are not limited to, thermogravimetricanalysis (“TGA”), differential scanning calorimetric (“DSC”), X-raypowder diffraction (“XRPD”), single crystal X-ray diffractometry,vibrational spectroscopy, e.g., IR and Raman spectroscopy, solid-statenuclear magnetic resonance (“NMR”), optical microscopy, hot stageoptical microscopy, scanning electron microscopy (“SEM,”) electroncrystallography and quantitative analysis, particle size analysis(“PSA”), surface area analysis, solubility studies and dissolutionstudies.

As used herein, the terms “polymorph” and “polymorphic form” refer toone of two or more crystal forms that comprise the same molecule,molecules or ions. Different polymorphs may have different physicalproperties such as, for example, melting temperatures, heats of fusion,solubilities, dissolution rates, and/or vibrational spectra as a resultof the arrangement or conformation of the molecules or ions in thecrystal lattice. The differences in physical properties exhibited bypolymorphs may affect pharmaceutical parameters, such as storagestability, compressibility, density (important in formulation andproduct manufacturing), and dissolution rate (an important factor inbioavailability). Differences in stability can result from changes inchemical reactivity (e.g., differential oxidation, such that a dosageform discolors more rapidly when comprised of one polymorph than whencomprised of another polymorph), mechanical changes (e.g., tabletscrumble on storage as a kinetically favored polymorph converts tothermodynamically more stable polymorph), or both (e.g., tablets of onepolymorph are more susceptible to breakdown at high humidity). As aresult of solubility/dissolution differences, in the extreme case, somepolymorphic transitions may result in lack of potency or, at the otherextreme, toxicity. In addition, the physical properties of a crystallineform may be important in processing; for example, one polymorph might bemore likely to form solvates or might be difficult to filter and washfree of impurities (e.g., particle shape and size distribution might bedifferent between polymorphs).

As used herein, the term “stereomerically pure” means a composition thatcomprises one stereoisomer of a compound and is essentially free ofother stereoisomers of that compound. In certain aspects,stereomerically pure Compound (I) or a salt or solvate thereof isprovided herein that is essentially free of the other stereoisomersincluding, for example,(R)-2-(3′-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4′-bipyridin]-2′-yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one.In certain aspects, a stereomerically pure compound comprises greaterthan about 80 percent by weight of one stereoisomer of the compound andless than about 20 percent by weight of other stereoisomers of thecompound, greater than about 90 percent by weight of one stereoisomer ofthe compound and less than about 10 percent by weight of the otherstereoisomers of the compound, greater than about 95 percent by weightof one stereoisomer of the compound and less than about 5 percent byweight of the other stereoisomers of the compound, greater than about 97percent by weight of one stereoisomer of the compound and less thanabout 3 percent by weight of the other stereoisomers, or greater thanabout 99 percent by weight of one stereoisomer of the compound and lessthan about 1 percent by weight of the other stereoisomers of thecompound. In certain aspects, term “stereomerically pure” compound (I)means that the compound is made up of approximately 100% by weight ofthis particular stereoisomer. The above percentages are based on thetotal amount of combined stereoisomers of the compound.

In the description herein, if there is a discrepancy between a depictedstructure and a name given to that structure, then the depictedstructure controls. Additionally, if the stereochemistry of a structureor a portion of a structure is not indicated with, for example, boldwedged, or dashed lines, the structure or portion of the structure is tobe interpreted as encompassing all stereoisomers of it. In some cases,however, where more than one chiral center exists, the structures andnames may be represented as single enantiomers to help describe therelative stereochemistry

As used herein, a crystalline or amorphous form that is “essentiallypure” contains less than about 10 percent by weight of one or more othercrystalline or amorphous form, less than about 5 percent by weight ofone or more other crystalline or amorphous form, less than about 3percent by weight of one or more other crystalline or amorphous form,less than about 1 percent by weight of one or more other crystalline oramorphous form, or less than about 0.5 percent by weight of one or moreother crystalline or amorphous form. In certain contexts, as usedherein, “essentially pure” compound (I) or a salt or solvate thereof canmean free of other chemical compounds, for example, unreacted precursorsand side products that might be present in preparation processes. Inother contexts, as used herein, a “essentially pure” solid form (e.g.,crystalline form or amorphous form) of compound (I) or a salt or solvatethereof can mean free of other solid forms of compound (I) or salts orsolvates thereof. As such, “essentially pure” compound (I) may comprise,in certain aspects, less than about 10%, 5%, 3%, 2%, 1%, 0.75%, 0.5%,0.25%, or 0.1% by weight of one or more other crystal forms andamorphous forms of the compound and/or other chemical compounds. Incertain aspects, a solid form that is essentially pure is essentiallyfree of one or more other particular crystal forms, amorphous forms,and/or other chemical compounds.

The terms “treat” and “treatment” refer to therapeutic treatment,wherein the object is to slow down (lessen) an undesired physiologicalchange or disorder, such as the development or spread of arthritis orcancer. For purposes of this disclosure, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. Those in need of treatment include those with the conditionor disorder.

The phrase “therapeutically effective amount” means an amount of acompound of the present disclosure that (i) treats the particulardisease, condition, or disorder, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease, condition, ordisorder, or (iii) prevents or delays the onset of one or more symptomsof the particular disease, condition, or disorder described herein. Inthe case of cancer, the therapeutically effective amount of the drug mayreduce the number of cancer cells; reduce the tumor size; inhibit (i.e.,slow to some extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., slow to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; and/orrelieve to some extent one or more of the symptoms associated with thecancer. To the extent the drug may prevent growth and/or kill existingcancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy,efficacy can be measured, for example, by assessing the time to diseaseprogression (TTP) and/or determining the response rate (RR).

“Inflammatory disorder” as used herein can refer to any disease,disorder, or syndrome in which an excessive or unregulated inflammatoryresponse leads to excessive inflammatory symptoms, host tissue damage,or loss of tissue function. “Inflammatory disorder” also refers to apathological state mediated by influx of leukocytes and/or neutrophilchemotaxis.

“Inflammation” as used herein refers to a localized, protective responseelicited by injury or destruction of tissues, which serves to destroy,dilute, or wall off (sequester) both the injurious agent and the injuredtissue. Inflammation is notably associated with influx of leukocytesand/or neutrophil chemotaxis. Inflammation can result from infectionwith pathogenic organisms and viruses and from noninfectious means suchas trauma or reperfusion following myocardial infarction or stroke,immune response to foreign antigen, and autoimmune responses.Accordingly, inflammatory disorders amenable to treatment with Formula Icompounds encompass disorders associated with reactions of the specificdefense system as well as with reactions of the nonspecific defensesystem.

The terms “cancer” refers to or describe the physiological condition inmammals that is typically characterized by unregulated cell growth. A“tumor” comprises one or more cancerous cells. Examples of cancerinclude, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma,and leukemia or lymphoid malignancies. More particular examples of suchcancers include squamous cell cancer (e.g., epithelial squamous cellcancer), lung cancer including small-cell lung cancer, non-small celllung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinomaof the lung, cancer of the peritoneum, hepatocellular cancer, gastric orstomach cancer including gastrointestinal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectalcancer, endometrial or uterine carcinoma, salivary gland carcinoma,kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer,hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head andneck cancer.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer, regardless of mechanism of action. Classes ofchemotherapeutic agents include, but are not limited to: alkylatingagents, antimetabolites, spindle poison plant alkaloids,cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies,photosensitizers, and kinase inhibitors. Chemotherapeutic agents includecompounds used in “targeted therapy” and conventional chemotherapy.Examples of chemotherapeutic agents include: erlotinib (TARCEVA®,Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU(fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®,Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin(cis-diamine, dichloroplatinum(II), CAS No. 15663-27-1), carboplatin(CAS No. 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology,Princeton, N.J.), trastuzumab (HERCEPTIN®, Genentech), temozolomide(4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide,CAS No. 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), tamoxifen((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine,NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYClNO), Akti-1/2,HPPD, and rapamycin.

More examples of chemotherapeutic agents include: oxaliplatin(ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent(SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, AstraZeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin(folinic acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib(TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR™, SCH66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs),gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11,Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.),vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chloranmbucil, AG1478,AG1571 (SU 5271; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib(GlaxoSmithKline), canfosfamide (TELCYTA®, Telik), thiotepa andcyclosphosphamide (CYTOXAN®, NEOSAR®); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, calicheamicin gamma1I, calicheamicin omegaI1 (Angew Chem.Intl. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A;bisphosphonates, such as clodronate; an esperamicin; as well asneocarzinostatin chromophore and related chromoprotein enediyneantibiotic chromophores), aclacinomysins, actinomycin, authramycin,azaserine, bleomycins, cactinomycin, carabicin, caminomycin,carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin,marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone;vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide;edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche);ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO); retinoids such as retinoic acid; andpharmaceutically acceptable salts, acids and derivatives of any of theabove.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifinecitrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase,which regulates estrogen production in the adrenal glands, such as, forexample, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrolacetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole,RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide,nilutamide, bicalutamide, leuprolide, and goserelin; as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) lipidkinase inhibitors; (vi) antisense oligonucleotides, particularly thosewhich inhibit expression of genes in signaling pathways implicated inaberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras, suchas oblimersen (GENASENSE®, Genta Inc.); (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; topoisomerase 1 inhibitorssuch as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptablesalts, acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” aretherapeutic antibodies such as alemtuzumab (Campath), bevacizumab(AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab(VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec),pertuzumab (OMNITARGT™, 2C4, Genentech), trastuzumab (HERCEPTIN®,Genentech), tositumomab (Bexxar, Corixia), and the antibody drugconjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “pharmaceutically acceptable” refers to components orexcipients which are not biologically or otherwise undesirable and whichare compatible chemically and/or toxicologically, with the otheringredients comprising a formulation, and/or the mammal being treatedtherewith.

Tablets

Some aspects of the disclosure relate to pharmaceutical tabletcompositions comprising compound (I) free base and an acid. In someaspects, the acid is an organic acid or an inorganic acid. In someaspects, the acid is an organic acid selected from fumaric acid, citricacid, succinic acid, and tartaric acid. In some particular aspects, theacid is fumaric acid.

The compound (I) free base content in the tablet composition is about 25mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg,about 250 mg or about 300 mg, and ranges thereof, such as from about 25mg to about 300 mg, from about 25 mg to about 200 mg, from about 25 mgto about 100 mg, from about 50 mg to about 150 mg, from about 100 mg toabout 200 mg, from about 100 mg to about 300 mg, or from about 150 mg toabout 250 mg. Based on tablet weight, the free base content in thetablet composition is about 5 wt. %, about 10 wt. %, about 15 wt. %,about 20 wt. %, about 25 wt. %, about 30 wt. %, about 35 wt. % or about40 wt. %, and ranges thereof, such as from about 5 wt. % to about 40 wt.%, from about 10 wt. % to about 40 wt. %, from about 15 wt. % to about35 wt. %, from about 15 wt. % to about 30 wt. %, or from about 20 wt. %to about 25 wt. %.

The organic acid (e.g., fumaric acid) content in the tablet compositionis about 5 wt. %, about 10 wt. %, about 15 wt. %, about 20 wt. %, about25 wt. %, about 30 wt. %, about 35 wt. %, about 40 wt. %, about 45 wt. %or about 50 wt. %, and ranges thereof, such as from about 5 wt. % toabout 50 wt. %, from about 5 wt. % to about 40 wt. %, from about 5 wt. %to about 30 wt. %, from about 5 wt. % to about 20 wt. %, from about 10wt. % to about 30 wt. %, from about 15 wt. % to about 25 wt. %, fromabout 20 wt. % to about 25 wt. %, from about 5 wt. % to about 15 wt. %,or from about 10 wt. % to about 15 wt. %. In some other aspects, fumaricacid is present as an extra-granular component in the tablet. In someother aspects, fumaric acid is present as an intra-granular component inthe tablet. In some other aspects, fumaric acid may be present as bothand intra-granular component and as an extra-granular component.

The weight ratio of the compound (I) free base to organic acid (fumaricacid) is about 1:5, about 1:4.5, about 1:4, about 1:3.5 about 1:3, about1:2.5, about 1:2, about 1:1.5, about 1:1, about 1.5:1, about 2:1, about2.5:1 or about 3:1, and ranges thereof, such as from about 1:5 to about3:1, from about 1:1 to about 1:5, from about 1:2 to about 1:5, fromabout 1:3 to about 1:5, from about 1:3 to about 3:1, from about 1:2 toabout 2:1, from about 1:1.5 to about 1.5:1, or from about 1.2:1 to about1:1.2.

Tablet weight is suitably about 100 mg, about 200 mg, about 300 mg,about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg,about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300mg, about 1400 mg or about 1500 mg.

In some aspects of the disclosure, the weight ratio of compound (I) freebase to fumaric acid is about 1:5, about 1:4, about 1:3, about 1:2,about 1:1, from about 1:1 to about 1:5, from about 1:2 to about 1:5 orfrom about 1:3 to about 1:5. In such aspects, compound (I) free basecontent is about 25 mg, about 50 mg, about 75 mg or about 100 mg, fromabout 25 mg to about 100 mg or from about 25 mg to about 50 mg. In suchaspects, as described in more detail elsewhere herein, the fumaric acidcontent in the tablet may be up to about 50 wt. %. In some other aspectsof the disclosure, the weight ratio of compound (I) free base to fumaricacid is about 2:1, about 1.5:1, about 1.2:1, about 1:1, about 1:1.2,about 1:1.5 or about 1:2, and ranges thereof, such as from about 2:1 toabout 1:2, from about 1.5:1 to about 1:1.5, or from about 1.2:1 to about1:1.2. In such aspects, compound (I) free base content is about 100 mg,about 150 mg, about 200 mg, about 250 mg, about 300 mg, and rangesthereof, such as from about 100 mg to about 300 mg or from about 150 mgto about 250 mg.

The tablets of the present disclosure provide for improved compound (I)free base pharmacokinetics in humans exhibiting achlorohydria ascompared to compound (I) free base formulated in the absence of anorganic acid. In vivo human achlorohydria pharmacokinetics for a tabletdosage comprising 200 mg compound (I) free base are as follows. In someaspects, the terminal half-life (t½) is about 5 hours, about 10 hours,about 15 hours, about 20 hours, or about 25 hours, and rangesconstructed from combinations of said values, for instance, from about 5to about 25 hours, from about 5 to about 20 hours, or from about 5 toabout 15 hours. In some aspects, the time to maximum plasmaconcentration (tmax) is about 0.5 hours, about 1 hour, about 2 hours,about 3 hours, or about 4 hours, and ranges constructed fromcombinations of said values, for instance, from about 0.5 to about 4hours, from about 0.5 to about 3 hours, or from about 1 to about 3hours. In some aspects, the maximum plasma concentration (Cmax) is about80 ng/mL, about 100 ng/mL, about 150 ng/mL, about 200 ng/mL, about 250ng/mL, about 300 ng/mL, about 350 ng/mL, about 400 ng/mL, about 450ng/mL, about 500 ng/mL, about 800 ng/mL, about 1000 ng/mL or about 1200ng/mL, and ranges constructed from combinations of said values, forinstance, from about 80 to about 1200 ng/mL, from about 200 to about1000 ng/mL, or from about 400 to about 800 ng/mL. In some aspects, theplasma concentration after 12 hours (C12) is about 20 ng/mL, about 30ng/mL, about 40 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL orabout 80 ng/mL, and ranges constructed from combinations of said values,for instance, from about 20 to about 80 ng/mL, from about 20 to about 60ng/mL, or from about 30 to about 50 ng/mL. In some aspects, the areaunder the concentration curve over the time period of dosing to 12 hours(AUC0-12) is about 500 h*ng/mL, about 1000 h*ng/mL, about 1500 h*ng/mL,about 2000 h*ng/mL, or about 2500 h*ng/mL, and ranges constructed fromcombinations of said values, for instance, from about 500 to about 2500h*ng/mL or 1000 to about 2000 h*ng/mL. In some aspects, the area underthe concentration curve over the time period of dosing to 24 hours(AUC0-24) is about 800 h*ng/mL, about 1000 h*ng/mL, about 1500 h*ng/mL,about 2000 h*ng/mL, about 2500 h*ng/mL, about 3000 h*ng/mL, about 3500h*ng/mL, or about 4000 h*ng/mL, and ranges constructed from combinationsof said values, for instance, from about 800 to about 4000 h*ng/mL, fromabout 1500 to about 3000 h*ng/mL, or from about 2000 to about 3000h*ng/mL. In some aspects, the area under the concentration curve overthe time period of dosing to ∞ (72 hours) (AUC0-∞) is about 900 h*ng/mL,about 1500 h*ng/mL, about 2000 h*ng/mL, about 2500 h*ng/mL, about 3000h*ng/mL, about 3500 h*ng/mL, about 4000 h*ng/mL, or about 4500 h*ng/mL,and ranges constructed from combinations of said values, for instance,from about 900 to about 4500 h*ng/mL, from about 1500 to about 4000h*ng/mL, or from about 2000 to about 3000 h*ng/mL.

The tablet compositions of the present disclosure may further suitablycomprise one or more pharmaceutically acceptable excipients selectedfrom, but not limited to fillers (diluents), disintegrants, binders,glidants, and lubricants. A filler (or diluent) may be used to increasethe bulk volume of the powdered drug making up the tablet. Adisintegrant may be used to encourage the tablet to break down intosmall fragments, ideally individual drug particles, when it is ingestedand thereby promote the rapid dissolution and absorption of drug. Abinder may be used to ensure that granules and tablets can be formedwith the required mechanical strength and hold a tablet together afterit has been compressed, preventing it from breaking down into itscomponent powders during packaging, shipping and routine handling. Aglidant may be used to improve the flowability of the powder making upthe tablet during production. A lubricant may be used to ensure that thetableting powder does not adhere to the equipment used to press thetablet during manufacture, to improve the flow of the powder duringmixing and pressing, and to minimize friction and breakage as thefinished tablets are ejected from the equipment.

Fillers and binders may include calcium hydrogenphosphate,microcrystalline cellulose (Avicel®), lactose, or any other suitablebulking agent. Examples of suitable fillers include microcrystallinecellulose, such as Avicel PH 101, Avicel PH102, Avicel PH 200, Avicel PH105, Avicel DG, Ceolus KG 802, Ceolus KG 1000, SMCCSO and Vivapur 200;lactose monohydrate, such as Lactose FastFlo; microcrystalline celluloseco-processed with other excipients, such as microcrystalline cellulosecoprocessed with lactose mono hydrate (MicroceLac 100) andmicrocrystalline cellulose co-processed with colloidal silicon dioxide(SMCCSO, Prosolv 50 and Prosolv HD 90); mixtures of isomaltulosederivatives such as galenIQ; and other suitable fillers and combinationsthereof. The filler may be present as an intra-granular component and/oras an extra-granular component. In some particular aspects, the tabletcompositions of the present disclosure comprise lactose andmicrocrystalline cellulose.

Disintegrants may be included in the disclosed formulations to promoteseparation of the granules within the compact from one another and tomaintain separation of the liberated granules from one another.Distintegrants may be present as an intra-granular component and/or asan extra-granular component. Disintegrants may include any suitabledisintegrant such as, for example, crosslinked polymers such ascross-linked polyvinyl pyrrolidone and cross-linked sodiumcarboxymethylcellulose or croscarmellose sodium. In some particularaspects, the disintegrant is croscarmellose sodium. The disintegrantcontent is suitably about 1 wt. %, about 1.5 wt. %, about 2 wt. %, about2.5 wt. %, about 3 wt. %, about 3.5 wt. %, about 4 wt. %, about 4.5 wt.%, or about 5 wt. %, and ranges thereof, such as from about 1 wt. % toabout 5 wt. %, or from about 2 wt. % to about 4 wt. %.

Glidants may include, for example, colloidal silicon dioxide, includinghighly dispersed silica (Aerosil®), or any other suitable glidant suchas animal or vegetable fats or waxes. In some particular aspects, theglidant is fumed silica. The glidant content is suitably about 0.1 wt.%, about 0.5 wt. %, about 1 wt. %, about 1.5 wt. %, about 2 wt. %, about2.5 wt. % or about 3 wt. %, and ranges thereof, such as from about 0.1wt. % to about 3 wt. %, from about 0.5 wt. % to about 2 wt. %, fromabout 0.5 wt. % to about 1.5 wt. %.

Lubricants may be used in compacting granules in the pharmaceuticalcomposition. Lubricants may include, for example, polyethylene glycol(e.g., having a molecular weight of from about 1000 to about 6000),magnesium and calcium stearates, sodium stearyl fumarate, talc, or anyother suitable lubricant. In some particular aspects, the lubricant ismagnesium stearate and/or sodium stearyl fumarate. The lubricant may bepresent as an intra-granular component and/or as an extra-granularcomponent. The lubricant content is suitably about 0.5 wt. %, about 1wt. %, about 1.5 wt. %, about 2 wt. %, about 2.5 wt. %, about 3 wt. %,about 3.5 wt. %, about 4 wt. %, about 4.5 wt. %, or about 5 wt. %, andranges thereof, such as from about 0.5 wt. % to about 5 wt. %, fromabout 1 wt. % to about 4 wt. %, from about 1 wt. % to about 3 wt. %, orfrom about 1 wt. % to about 2 wt. %.

A coating, such as a film coating, may be applied to the tablets of thepresent disclosure. A film coat may be used to, for example, contributeto the ease with which the tablet can be swallowed. A film coat may alsobe employed to improve taste and appearance. If desired, the film coatmay be an enteric coat. The film coat may comprise a polymericfilm-forming material such as hydroxypropyl methylcellulose,hydroxypropyl cellulose, acrylate or methacrylate copolymers, andpolyvinyl alcohol-polyethylene glycol graft copolymers such as Opadryand Kollicoat IR. In addition to a film-forming polymer, the film coatmay further comprise a plasticizer, e.g. polyethylene glycol, asurfactant, e.g. a Tween® type, and optionally a pigment, e.g. titaniumdioxide or iron oxides. The film-coating may also comprise talc as ananti-adhesive. The film coat typically accounts for less than about 5%by weight of the dosage form.

In some aspects of the disclosure, tablets may be prepared by a processcomprising pre-blending, direct tablet compression, and coating. In someother aspects, tablets may be prepared by a process comprising (i)pre-blending, (ii) granulation and sizing, such as by roller compactionand milling or by dry granulation, (iii) blending/lubrication, (iv)tablet compression, and (v) coating.

Pre-blending is designed to provide substantial homogeneity of theintra-granular components prior to roller compaction. Pre-blendingequipment and related process parameters that provide for essentiallyhomogeneous blends are known to those skilled in the art. Suitableblenders are known in the art and any apparatus typically employed inthe pharmaceutical industry for uniformly admixing two or morecomponents including V-shaped blenders, double-cone blenders, bin(container) blenders, and rotary drum blenders. The combination blendervolume, blender fill, rotation speed and rotation time may be suitablydetermined by those skilled in the art in order to achieve anessentially homogeneous admixture of components. Blender volume issuitably about 2 L, about 50 L, about 100 L, about 200 L, about 250 L,about 500 L, about 650 L or about 1000 L. Selection of blender fillallows for convection and three-dimensional material movement, and issuitably about 25%, about 30%, about 35%, about 40%, about 50%, about60% or about 70%, and ranges thereof, such as from about 30% to about60%, from about 45% to about 65%, from 32% to 53% or from 32% to 40%.Blend time is suitably, 5 min, 10 min, 15 min, 20 min, 30 min, 40 min,50 min, 60 min, or more. Rotation rate is suitably, for instance, 2 rpm,3 rpm, 4 rpm, 5 rpm, 6 rpm, 7 rpm, 8 rpm, 9 rpm or 10 rpm.

Granulation and sizing may be achieved using any suitable method knownto those skilled in the art. In some particular aspects of thedisclosure, granulation and sizing comprises dry granulation, millingand screening (sieving). In some other aspects of the disclosure, drygranulation is roller compaction. Granulation and sizing improves flowand compression characteristics of the admixture of active drug andexcipients. Roller compaction is a process wherein pre-blend powderparticles are made to adhere together resulting in larger, granularmulti-particle entities. Roller compaction generally comprises threeunit operations including a feeding system, a compaction unit and amilling/sieving unit. In the compaction unit, the pre-blend is compactedbetween counter-rotating rolls by application of a roller compactionforce (expressed in kN/cm) to form a formed mass of compacted material,such as a ribbon or a sheet. The distance between the rolls is definedas the gap width. The formed ribbon of compacted material is processedin a size reduction unit by milling to form granules that are screenedto produce a plurality of granules having a desired particle sizedistribution.

Roller compaction and milling equipment is available commercially from anumber of manufacturers including Gerteis, Fitzpatrick® andFreund-Vector. Such equipment generally provides for control of rollercompaction force, gap width, roller speed and feed rate. The rollersurfaces may be smooth, knurled, or one roller surface may be smooth andthe other roller surface may be knurled. In any of the various aspects,the pre-blend is charged to a roller compactor feed hopper. Rollercompaction is performed at a specified force and gap size, and theprocess is preferably run under gap control. In any of the variousaspects of the disclosure, the gap size is about 2 mm, about 3 mm, about4 mm or about 5 mm, or more, and ranges thereof, such as from about 2 mmto about 5 mm, from about 2 mm to about 4 mm, from about 3 mm to about 5mm or from about 4 mm to about 5 mm. The roller compaction force isabout 1 kN/cm, about 2 kN/cm, about 3 kN/cm, about 4 kN/cm, about 5kN/cm, about 6 kN/cm, about 7 kN/cm or about 8 kN/cm, or more, andranges thereof, such as from about 1 kN/cm to about 8 kN/cm, from about2 kN/cm to about 5 kN/cm or from about 2 kN/cm to about 4 kN/cm. Theformed ribbons or sheet may be milled through a screen to producegranules. In some aspects of the disclosure, the screen is integral tothe mill. In any of the various aspects of the disclosure, the millingscreen size is 0.5 mm, 0.75 mm, 1.0 mm, 1.25 mm, 1.5 mm, 1.75 mm, 2.0mm, 2.25 mm or 2.5 mm, and ranges thereof, such as from about 0.5 mm toabout 2.5 mm, from about 0.5 mm to about 2.0 mm, from about 0.5 mm toabout 1.5 mm, from about 0.5 mm to about 1.25 mm, from about 0.75 mm toabout 2.5 mm, from about 0.75 mm to about 2.0 mm, from about 0.75 mm toabout 1.5 mm, or from about 0.75 mm to about 1.25 mm.

In the final blending step, granules formed by roller compaction andmilling are charged to a blender and any extra-granular component, suchas disintegrant (e.g., croscarmellose sodium) and lubricant (e.g.,magnesium stearate or sodium stearyl fumarate), and optionally organicacid (e.g., fumaric acid), is added to the blender to form an admixture.The final blending step provides for an essentially homogeneousdistribution of any external disintegrant and lubricant and provides foracceptable processability during tablet compression. Suitable blendersand related process variables are described above.

Filler, lubricant and disintegrants are typically delumped by screeningprior to blending. Screening methods are known to this skilled in theart. In an example of one particular pre-blend aspect of the disclosure,filler (e.g. lactose monohydrate and MCC) and disintegrant (e.g.,croscarmellose sodium) are delumped by screening and are combined withcompound (I) in a blender, and the blender contents are blended for ablend time (e.g., 30 minutes) at a fixed rotation rate (e.g., 6 rpm).Lubricant (e.g., magnesium stearate) is delumped by screening and isadded to a blender containing admixed filler, disintegrant and compound(I). The blender contents are blended for a blend time (e.g., 2 minutesto 30 minutes) at a fixed rotation rate (e.g., 5 rpm to 10 rpm) to formthe pre-blend.

In the tableting step, a tableting die mold is filled with final blendmaterial and the mixture is compressed to form a tablet core that isejected. Suitable tablet presses are known in the art and are availablecommercially from, for instance, Riva-Piccola, Carver, Fette, BoschPackaging Technology, GEA and Natoli Engineering Company. Generally,each tablet is made by pressing the granules inside a die, made up ofhardened steel. The die is typically a disc shape with a hole cutthrough its center. The powder is compressed in the center of the die bytwo hardened steel punches that fit into the top and bottom of the diethereby forming the tablet. Tablet compression may be done in two stageswith the first, pre-compression, stage involving tamping down the powderand compacting the blend slightly prior to application of the maincompression force for tablet formation. The tablet is ejected from thedie after compression.

Main compression force affects tablet characteristics such as hardnessand appearance. Main compression force further has an impact on stickingof the final blend to tablet tooling during compression, with increasedforce leading to reduced sticking and, hence, fewer tablets withappearance defects. Further, the compressibility of the final blend canimpact the quality (such as the presence or lack of defects) of theresultant tablet core. Compression processing parameters, such ascompression force and run time, can also have an impact. In some aspectsof the disclosure, the compression force is about 5 kN, about 6 kN,about 7 kN, about 8 kN, about 9 kN, about 10 kN, about 11 kN, about 12kN, about 13 kN, about 14 kN, about 15 kN, about 16 kN, about 17 kN,about 18 kN, about 19 kN, about 20 kN, or more, and ranges thereof, suchas from about 5 kN to about 20 kN, from about 14 kN to about 19 kN, fromabout 14 kN to about 18 kN, or from about 8 kN to about 13 kN.

The tablet cores may be film-coated to ensure that tablets areessentially tasteless and odorless, and are easy to swallow. Filmcoating also prevents dust formation during packaging and ensuresrobustness during transportation. Film coating may suitably be done bymethods known in the art such as by pan coating. Suitable coatingequipment includes, without limitation, a Glatt GC1000S.

In some aspects of the disclosure, tablet cores are charged to a coatingpan and warmed to a target temperature. The coating suspension isprepared to a target solids content. Once the tablets are within thetarget temperature range, drum rotation and spraying are runs at targetrates designed to achieve predetermined weight gain of about 3 wt. %,about 4 wt. % or about 5 wt. %. Outlet air temperature is maintained ina range to ensure that the target product temperature is obtainedthroughout coating. Once spraying is complete, the coated tablets aredried and cooled down before discharging the film-coated tablets. Asolid content of a coating suspension is suitably from about 10 wt. % toabout 20 wt. %, or from about 15 wt. % to about 20 wt. %. The coatingspray rate per kg of tablet cores is suitably about 0.5 g/min to about2.5 g/min, or from about 1 g/min to about 2 g/min. The coatingtemperature is suitably from about 30° C. to about 60° C., or from about40° C. to about 50° C. The pan rotational speed is suitably from about 2to about 20 rpm, from about 4 to about 15 rpm, or from about 8 to about12 rpm. The inlet air volume varies with the batch size and is suitablyfrom about 300 to about 1500 m3/h, from about 450 to about 1200 m3/h, orfrom about 1000 to about 1250 m3/h.

Amorphous Solid Dispersions

In general, amorphous solid dispersions of the present disclosurecomprise a polymeric component and from about 20 wt. % to about 60 wt. %of compound (I) free base. In some aspects, the content of compound (I)free base is from about 30 wt. % to about 50 wt. %, from about 40 wt. %to about 50 wt. %, or about 50 wt. %. In some aspects, the glasstransition temperature of the amorphous solid dispersions is at least115° C., at least 125° C., or at least 150° C., such as 100° C., about110° C., about 120° C., about 130° C., about 140° C., about 150° C.,about 160° C., or about 170° C.

The amorphous solid dispersions may be characterized by aqueousdissolution at about pH 1 that is representative of normal stomach pH,at a pH of from about 4 to about 6 that is representative ofachlorhydria stomach pH, and/or at a pH of from about 6.5 to about 7that is representative of intestinal pH. More particularly, thedissolution of the compound (I) free base contained in amorphous soliddispersions in aqueous pH 1 buffer at 37° C. after 20 minutes is fromabout 1 mg/mL to about 2 mg/mL or from 1 mg/mL to about 1.5 mg/mL. Thedissolution of the free base compound contained in the amorphous soliddispersion in aqueous pH 4.5 buffer at 37° C. after 20 minutes is atleast 0.1 mg/mL, at least 0.2 mg/mL, at least 0.3 mg/mL, or from about0.1 mg/mL to about 0.35 mg/mL. The dissolution of the free base compoundcontained in the amorphous solid dispersion in pH 6.8 fasted-statesimulated intestinal fluid media at 37° C. after 60 minutes and after180 minutes is at least 0.05 mg/mL, at least 0.075 mg/mL, or from about0.075 mg/mL to about 0.1 mg/mL.

In some optional aspects of the present disclosure, the amorphous soliddispersions of the present disclosure may further comprise an acid. Insuch aspects, the molar equivalent ratio of the acid to the free base isfrom about 1:1 to about 10:1, from about 2:1 to about 10:1, from about2:1 to about 5:1, from about 2:1 to about 4:1, or about 3:1. The acidmay suitably be an organic acid or an inorganic acid. Suitable organicacids include, but are not limited to, fumaric acid, succinic acid,citric acid, and tartaric acid. Suitable inorganic acids include, butare not limited to, hydrochloric acid and sulfuric acid.

Amorphous solid dispersions comprising an acid may be characterized byaqueous dissolution at about pH 1, at a pH of about 4.5, and/or at a pHof about 6.8 as described elsewhere herein. More particularly, thedissolution of the free base compound contained in the amorphous soliddispersion in aqueous pH 1 buffer at 37° C. after 20 minutes is at least1.5 mg/mL, at least 2 mg/mL or from about 2 mg/mL to about 2.5 mg/mL.The dissolution of the free base compound contained in the amorphoussolid dispersion in aqueous pH 4.5 buffer at 37° C. after 20 minutes isat least 1 mg/mL, at least 1.25 mg/mL, or from about 1 mg/mL to about1.5 mg/mL. The dissolution of the free base compound contained in theamorphous solid dispersion in pH 6.8 fasted-state simulated intestinalfluid media at 37° C. after 60 minutes and after 180 minutes is at least0.05 mg/mL, or from about 0.05 mg/mL to about 0.08 mg/mL.

Non-limiting examples of polymers suitable for use singularly or incombination include alkylcellulose, hydroxyalkylcelluloses,hydroxyalkylalkylcellulose, methylcellulose (MC), ethylcellulose (EC),hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyethylmethylcellulose (HEMC),hydroxypropylmethylcellulose succinate, hydroxypropylmethyl celluloseacetate succinate (HPMCAS), carboxymethylethylcellulose, sodiumcarboxymethylcellulose, potassium carboxymethyl cellulose, celluloseacetate succinate, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, polyacrylic acid copolymer,poly(meth)acrylic acid polymers, poly(hydroxyalkyl acrylates),poly(hydroxyalkyl methacrylates), polyvinylpyrrolidone (PVP),homopolymers of vinylpyrrolidone, copolymers of vinylpyrrolidone,povidone, vinylpyrrolidone-vinylacetate copolymer (copovidone),copolymers of vinyl acetate, copolymers of vinyl propionate, copolymersof vinyl acetate and crotonic acid, polyethylene glycol, polyvinylalcohol, partially hydrolyzed polyvinyl acetate, gelatin, sodiumalginate, soluble starch, gum acacia, dextrin, hyaluronic acid, sodiumchondroitin sulfate, propylene glycol alginate, agar, tragacanth,xanthan gum, aminoalkyl methacrylate copolymers,polyvinyl-acetal-diethylaminoacetate, methacrylate copolymer, aminomethacrylate copolymer, methacrylic acid copolymer L, methacrylic acidcopolymer LD, methacrylic acid copolymer S, macrogol, polyethyleneoxide, polypropylene oxide, copolymers of ethylene oxide (EO) andpropylene oxide (PO), carrageenans, galactomannans, and Soluplus®.Soluplus® is a polyethylene glycol, polyvinyl acetate andpolyvinylcaprolactam-based graft copolymer available from BASF. In someparticular aspects, the polymeric component is suitably selected fromselected from polyvinylpyrrolidone, copovidone, hydroxypropyl methylcellulose, hypromellose acetate succinate, amino methacrylate copolymer,Soluplus®, and combinations thereof.

The amorphous solid dispersions of the present disclosure may beprepared by any process which results in compound (I) being essentiallyin the amorphous state and essentially homogeneously dispersedthroughout the polymer. Examples of methods for preparing amorphoussolid dispersions include melt-extrusion processes and solventprocessing methods such as spray drying and precipitation from solutionwith an anti-solvent.

In solvent processing methods, components comprising compound (I) andone or more polymers are dissolved in a solvent or solvent system inwhich the components are soluble. After dissolution, the solvent israpidly removed by evaporation or amorphous solid dispersions areprecipitated by mixing with an anti-solvent. Exemplary processes includespray-drying, spray-coating (pan-coating, fluidized bed coating, etc.),and precipitation by rapid admixing the solution with CO₂ or ananti-solvent. Preferably, the process comprises solvent removal toprovide a solid solution of compound (I) dispersed in the polymer(s).

Suitable solvents can be any organic compound in which compound (I) andthe polymer(s) are mutually soluble. Preferably, the solvent is volatileand has a boiling point of no more than 150° C. A non-exclusive list ofsolvents includes: alcohols such as methanol, ethanol, n-propanol,i-propanol, n-butanol and i-butanol; ketones such as acetone, methylethyl ketone and methyl i-butyl ketone; esters such as ethyl acetate andpropylacetate; and other solvents such as acetonitrile, methylenechloride, toluene, and 1,1,1-trichloroethane. Lower volatility solventssuch as dimethyl acetamide or dimethylsulfoxide can also be used.Mixtures of solvents, such as 50% methanol and 50% acetone, can also beused. In some aspects, the solvent system comprises water in combinationwith an organic solvent at a volume ratio of organic solvent to water ofabout 80:20, about 85:15, about 90:10 or about 95:5. Non-limitingexamples of such solvent systems include acetone and water and methanoland water.

In spray-drying methods, in a spray-drying apparatus, a solutioncomprising compound (I) and at least one polymer is atomized into smalldroplets and the solvent is rapidly removed by evaporation to yield acrude amorphous solid dispersion. A rapid solvent evaporation rate istypically achieved by maintaining the partial pressure of solvent in thespray-drying apparatus well below the vapor pressure of the solvent atthe temperature of the drying droplets through (1) maintaining thepressure in the spray-drying apparatus at a partial vacuum (such as fromabout 0.01 to about 0.50 atm), (2) mixing the liquid droplets with awarm drying gas, or (3) a combination thereof. Spray drying methods areknown in the art (see, e.g., Perry's Chemical Engineers' Handbook,Eighth Edition, McGraw-Hill, 2007) and spray drying equipment iscommercially available such as from Glatt, Freund-Vector andFitzpatrick. Generally, drying gas temperature and flow rate andatomized droplet size are selected to provide formed amorphous soliddispersion particulate that is sufficiently dry by the time it reachesthe spray drying apparatus chamber wall such that a fine powder thatdoes not appreciably adhere to the wall. The actual length of time toachieve this level of dryness depends, in part, on the size of thedroplets. Droplet size diameter generally ranges from about 1 μm toabout 500 μm, from about 1 μm to about 100 m, from about 1 μm to about50 μm, or from about 1 μm to about 25 μm. Typically, a large dropletsurface-to-volume ratio and a large driving force for solventevaporation provides for drying times of a few seconds or less. It isbelieved that a rapid drying rate provides for a homogeneous drugdispersion within the polymer matrix as compared to slower drying ratewherein some phase separation into drug-rich and polymer-rich phasescould occur. In general, amorphous solid dispersion particulateformation times should be less than about 100 seconds, less than about10 seconds, or even less than about 1 second.

In some aspects of the disclosure, the amorphous solid dispersion isprepared by melt extrusion comprising the steps of preparing ahomogeneous melt comprising compound (I) and one or more polymers andsolidifying the melt by cooling. In some aspects, the melt may furthercomprise one or more solubilizers. In general “melting” refers to atransition of a compound (I)-polymer admixture into a liquid or rubberystate in which compound (I) is homogeneously distributed within a matrixof the polymer. In melt extrusion, it is believed that the polymer(s)melts and compound (I) dissolves in the melt to form a solution. Meltcomponent mixing can take place before, during or after the formation ofthe melt. For instance, the components can be mixed first and thenmelted or simultaneously mixed and melted. Typically, the melt ishomogenized in order to improve compound (I) dispersion efficiency. Insome optional aspects, the polymer may be melted and compound (I) issubsequently added, admixed and homogenized. Melt temperature is afunction of the identity of the polymer(s) and compound (I) loading.Generally, the melt temperature is from about 70° C. to about 250° C.,from about 80° C. to about 180° C., or from about 100° C. to about 140°C.

Compound (I) may be in the form of a solid, a solution, or dispersion ina suitable solvent such as described elsewhere herein. When solvent ispresent, at least a portion of the solvent is evaporated or flashed offupon preparation of the melt. Various additives may be included in themelt, for instance, flow regulators (e.g., colloidal silica),lubricants, bulking agents (fillers), disintegrants, plasticizers,stabilizers (e.g., antioxidants), light stabilizers, radical scavengers,preservatives (e.g., biocides), and combinations thereof.

Melt extrusion processing methods and equipment are known in the art.Particularly suitable are extruders or kneaders. Suitable extrudersinclude single screw extruders, intermeshing screw extruders, andmulti-screw extruders. In some aspects, the extruder is a co-rotating orcounter-rotating twin screw extruder that may optionally be equippedwith kneading disks or other screw elements for mixing or dispersing themelt. Extruders are typically heated by a heating element and/or by ajacketed section through which steam or heated oil is passed in order toprovide at least a portion of the energy required to melt, mix anddissolve the components. Heat generated by friction and shearing of thematerial in the extruder may also provide a substantial amount of energyto the mixture and aid in the formation of a homogeneous melt of thecomponents.

Extruder extrudate morphology may suitably range from pasty to viscous.In some aspects, prior to solidification, the extrudate may be directlyshaped into tablets such as by a calender comprising twocounter-rotating rollers with mutually matching depressions on theirsurface. A broad range of tablet forms can be attained by using rollerswith different forms of depressions. In some aspects, films can beformed using rollers not having depressions on their surface. In someother aspects, extrudate may molded into a desired shape byinjection-molding. In yet other aspects, extrudate may be subjected toprofile extrusion through a die and cut into pieces, either beforesolidification (hot-cut) or after solidification (cold-cut).

In some aspects, the melt extrude amorphous solid dispersion materialmay milled or ground to granules as described elsewhere herein. Thegranules may then be filled into capsules or may be tableted. Suitablefilled capsule and tablet excipients and methods for preparation aredescribed elsewhere herein.

The ASD compositions of the present disclosure provide for improvedcompound (I) free base dissolution as compared to compound (I) free basealone. The dissolution of compound (I) free base formulated in an ASDcomposition in aqueous pH 1 buffer at 37° C. after 20 minutes is fromabout 1 mg/mL to about 2 mg/mL or from 1 mg/mL to about 1.5 mg/mL. Thedissolution of compound (I) free base formulated in an ASD compositionin aqueous pH 4.5 buffer at 37° C. after 20 minutes is at least 0.1mg/mL, at least 0.2 mg/mL, at least 0.3 mg/mL, or from about 0.1 mg/mLto about 0.35 mg/mL. The dissolution of compound (I) free baseformulated in an ASD composition in aqueous pH 4.5 buffer at 37° C.after 20 minutes is at least 0.1 mg/mL, at least 0.2 mg/mL, at least 0.3mg/mL, or from about 0.1 mg/mL to about 0.35 mg/mL.

The ASD compositions of the present disclosure further comprising anacid provide for improved compound (I) free base dissolution at pH 4 to5 as compared to compound (I) free base alone. The dissolution ofcompound (I) free base formulated in an ASD composition in aqueous pH 1buffer at 37° C. after 20 minutes is at least 1.5 mg/mL, at least 2mg/mL or from about 2 mg/mL to about 2.5 mg/mL. The dissolution ofcompound (I) free base formulated in an ASD composition in aqueous pH4.5 buffer at 37° C. after 20 minutes is at least 1 mg/mL, at least 1.25mg/mL, or from about 1 mg/mL to about 1.5 mg/mL. The dissolution ofcompound (I) free base formulated in an ASD composition in pH 6.8fasted-state simulated intestinal fluid media at 37° C. after 60 minutesand after 180 minutes is at least 0.05 mg/mL, or from about 0.05 mg/mLto about 0.08 mg/mL.

The ASD compositions of the present disclosure further provide forimproved pharmacokinetics at pH 4 to 5 as compared to compound (I) freebase alone. The ASD compositions provide for an in vitro Cmax at pH 4 to5 of at least 200 μM, at least 300 μM, at least 400 μM, at least 500 μM,at least 600 μM, at least 700 μM, at least 800 μM or at least 900 μMCmax. The ASD compositions provide for an in vitro AUC at pH 4 to 5 ofat least 5,000 hr*μM, at least 10,000 hr*μM, at least 15,000 hr*μM, atleast 20,000 hr*μM, at least 25,000 hr*μM, or at least 25,000 hr*μM. TheASD compositions provide for an in vitro Cmax at intestinal pH of atleast 100 μM, at least 150 μM, at least 200 μM, or at least 250 PM. TheASD compositions provide for an in vitro AUC at intestinal pH of atleast 10,000 hr*μM, at least 15,000 hr*μM, at least 20,000 hr*μM, atleast 25,000 hr*μM or at least 30,000 hr*μM.

Compound (I) Salts

In some aspects, crystalline mesylate, chloride and sulfate salts ofcompound (I) are provided.

Compound (I) mesylate salt Form A is generally prepared by a processcomprising: (i) forming a solution of compound (I) free base Form A in asuitable solvent, (ii) combining the solution with a stoichiometricexcess of methanesulfonic acid to form compound (I) mesylate salt insolution, (iii) formation of compound (I) mesylate salt Form A bycrystallization, (iv) isolation of crystallized compound (I) mesylatesalt Form A, (v) optionally washing of the isolated compound (I)mesylate salt Form A, and (vi) drying. Suitable solvents include polarprotic solvents such as methanol, ethanol, isopropyl alcohol and aceticacid, polar aprotic solvents such as dichloromethane (“DCM”),tetrahydrofuran (“TIF”), ethyl acetate, acetonitrile (“ACN”),dimethylformamide (“DMF”), dimethyl sulfoxide and acetone, andcombinations thereof. In some aspects, the solvent is a solvent systemcomprising one or more polar protic and/or polar aprotic solvents andwater. In some aspects, the solvent is methanol, ethanol or isopropylalcohol. In some other aspects, the solvent is ethanol. The compound (I)free base concentration in the solvent is suitably about 0.05 mmol/mL,about 0.1 mmol/mL, about 0.15 mmol/mL, about 0.2 mmol/mL, about 0.25mmol/mL, about 0.3 mmol/mL, about 0.4 mmol/mL, about 0.5 mmol/mL, about0.6 mmol/mL, or about 0.7 mmol/mL. The dissolution temperature issuitably about 45° C., about 50° C., about 55° C., about 60° C., about65° C., or about 70° C. Methanesulfonic acid is added in stoichiometricexcess and the mole ratio of compound (I) free base to methanesulfonicacid is suitably about 1:1.01, about 1:1.05, about 1:1.1, about 1:1.15,or about 1:2. In some aspects, after methanesulfonic acid addition, thesolution is cooled to less than about 50° C., such as about 45° C.,about 40° C., about 35° C., or about 30° C. and held at that temperaturesuch as for about 5 minutes, about 10 minutes, about 15 minutes, about30 minutes, about 45 minutes, about one hour, or more. The cooledsolution is seeded with compound (I) mesylate salt Form A crystals toform a slurry and held with agitation for about 30 minutes, about onehour, about 2 hours, about 3 hours, or more. Seed crystal amount issuitably about 0.5 wt. %, about 1 wt. %, about 2 wt. %, about 3 wt. %,about 4 wt. % or about 5 wt. % based on the amount of compound (I) freebase. The seeded mixture is cooled at a controlled rate to about 5° C.,about 10° C., about 15° C., about 20° C., or about 25° C. wherein thecooling rate is suitably about 0.05° C./min, about 0.1° C./min, about0.15° C./min, about 0.2° C./min, about 0.5° C./min or about 1° C./min.The cooled mixture is held with agitation at temperature for about 1hour, about 5 hours, about 10 hours, about 15 hours, or about one day.Compound (I) mesylate salt Form A crystals may be suitably isolated andcollected by solid-liquid separation techniques known in the art such asfiltration and centrifugation. The collected crystals may be dried bytechniques known in the art, such as vacuum drying at a temperature ofless than about 50° C. In some aspects, crystallization is induced orpromoted by the addition of an anti-solvent to the slurry comprisingcompound (I) mesylate salt in solution and compound (I) mesylate saltForm A seed crystals prior to the final cooling step. Selection of asuitable anti-solvent relates to the identity of the solvent system. Insome aspects, suitable anti-solvents include non-polar solvents such aspentane, heptane, hexane and diethyl ether. The amount of anti-solventto solvent is suitably about 0.25:1 v/v, about 0.5:1 v/v, about 0.75:1v/v, about 1:1 v/v, about 1:1.5 v/v, about 1:2 v/v, or about 1:4. Theyield of compound (I) mesylate salt free base is suitably greater than90%.

In certain aspects, the compound (I) mesylate crystalline salt formprovided herein is essentially pure. For instance, in various aspects,the crystalline mesylate salt purity is of at least about 90%, at leastabout 95%, at least about 97%, at least about 98%, at least about 99%,at least about 99.2%, at least about 99.5%, at least about 99.6%, atleast about 99.7% or at least about 99.8% by weight of a singlecrystalline form, the remainder of the total weight which may be othercrystalline or amorphous forms and/or other compounds. In some aspects,the equivalent ratio of compound (I) to metsylate anion is about 1:1.

In one aspect, the crystalline mesylate salt is essentially asingle-component crystalline form or a single polymorph. In aspects, thecrystalline form is essentially free of an amorphous form of compound(I). In certain aspects, a crystalline mesylate salt of compound (I) isprovided having an XRPD pattern comprising one or more (e.g. one, two,three, four, five, six, seven, eight, nine, ten, or greater than ten; orat least three, at least four, at least five, at least six, or at leastseven) characteristic peaks selected from peaks with 2θ angle degreesaccording to table 4. In certain aspects, the crystalline mesylate salthas an XRPD pattern essentially as provided in FIG. 3B. In otheraspects, the crystalline mesylate salt has an XRPD pattern comprisingone or more peaks (e.g., at least three, at least four, at least five,at least six, or at least seven peaks) selected from peaks with 2θ angledegrees±0.2 2θ angle degrees of about 3.78, about 6.48, about 7.91,about 9.92, about 11.89, about 14.26, about 15.12, about 15.89, about17.24, about 18.10, about 19.86, about 20.55 and about 21.41. In otheraspects, the crystalline mesylate salt has an XRPD pattern comprisingone or more peaks (e.g., at least three, at least four, at least five,at least six, or at least seven peaks) selected from peaks expressed ind-values (A) of about 23.35, about 13.63, about 11.18, about 8.92, about7.44, about 6.21, about 5.86, about 5.58, about 5.14, about 4.90, about4.47, about 4.32 and about 4.15.

In some aspects, the crystalline mesylate salt exhibits two endothermalpeaks on DSC between room temperature and about 300° C., where a firstendothermal peak occurs between about 110° C. to about 125° C., betweenabout 115° C. to about 120° C., or from about 117° C. to about 118° C.and where a second endothermal peak occurs at between about 210° C. toabout 225° C., between about 214° C. to about 219° C. from, or fromabout 216° C. to about 218° C. In certain aspects, the crystallinemesylate salt has a DSC pattern essentially as provided in FIG. 7.

In certain aspects, the crystalline mesylate salt of compound (I) has adynamic vapor sorption (“DVS”) isotherm plot corresponding essentiallyto the DVS isotherm plot of FIG. 4. In certain aspects, a crystallinemesylate salt of compound (I) as provided herein does not exhibitsignificant weight change (e.g., less than about 0.05 wt. %, less thanabout 0.1 wt. %, less than about 0.15 wt. %, or less than about 0.2 wt.%) from about 0% to about 95% relative humidity.

In some aspects, compound (I) chloride salts are provided. In someaspects, compound (I) chloride salt Form A is generally prepared by aprocess comprising: (i) forming a solution of compound (I) free baseForm A in a suitable solvent, (ii) combining the solution with astoichiometric excess of hydrochloric acid to form compound (I) chloridesalt in solution, (iii) formation of compound (I) chloride salt Form Aby crystallization, (iv) isolation of crystallized compound (I) chloridesalt Form A, (v) optionally washing of the isolated compound (I)chloride salt Form A, and (vi) drying. Suitable solvents include polarprotic solvents and polar aprotic solvents as described elsewhereherein. In some aspects, the solvent is a solvent system comprising oneor more polar protic and/or polar aprotic solvents and water. In someaspects, the solvent is THF or ACN. In some particular aspects, thesolvent is a solvent system comprising tetrahydrofuran and water whereinthe v/v ratio of THF to water is about 5:1, about 10:1, about 15:1,about 19:1 or about 20:1, and ranges thereof. In some other particularaspects, the solvent system comprises THF, water and ACN. The compound(I) free base concentration in the solvent is suitably about 0.05mmol/mL, about 0.1 mmol/mL, about 0.15 mmol/mL, about 0.2 mmol/mL, about0.25 mmol/mL, about 0.3 mmol/mL, about 0.4 mmol/mL, about 0.5 mmol/mL,about 0.6 mmol/mL, or about 0.7 mmol/mL. The dissolution temperature issuitably about 20° C., about 25° C., about 30° C., about 35° C., about40° C., about 45° C., about 50° C., about 55° C., about 60° C., about65° C., or about 70° C. HCl is added in stoichiometric excess and themole ratio of compound (I) free base to HCl is suitably about 1:1.01,about 1:1.05, about 1:1.1, about 1:1.15, or about 1:2. The HCl issuitably about 0.1 M, about 0.20 M, about 0.3 M or about 0.4 M. In someaspects, the HCl is prepared by diluting concentrated HCl with thesolvent used to dissolve compound (I) free base (e.g., THF). In someother aspects, the HCl is prepared by diluting concentrated HCl withethanol. In some aspects, after HCl addition, the solution is cooled toless than about 50° C., such as about 45° C., about 40° C., about 35°C., or about 30° C. and held at that temperature such as for about 5minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45minutes, about one hour, or more. The solution is seeded with compound(I) chloride salt Form A crystals to form a slurry. Seed crystal amountis suitably about 0.5 wt. %, about 1 wt. %, about 2 wt. %, about 3 wt.%, about 4 wt. % or about 5 wt. % based on the amount of compound (I)free base. In some aspects, the solution is seeded and crystallized at atemperature of, about 5° C., about 10° C., about 15° C., about 20° C.,about 25° C. or about 25° C. The cooled mixture is held with agitationat temperature for about 10 hours, about 18 hours, about one day, about2 days, or longer. Compound (I) chloride salt Form A crystals may besuitably isolated and collected by solid-liquid separation techniquesknown in the art such as filtration and centrifugation. The collectedcrystals may be dried by techniques known in the art, such as vacuumdrying at a temperature of less than about 50° C. In some aspects,crystallization may be induced or promoted by the addition of ananti-solvent to the slurry comprising compound (I) chloride salt insolution and compound (I) chloride salt Form A seed crystals prior tothe final cooling step. Selection of a suitable anti-solvent relates tothe identity of the solvent system. In some aspects, suitableanti-solvents include non-polar solvents such as pentane, heptane,hexane and diethyl ether. The amount of anti-solvent to solvent issuitably about 0.25:1 v/v, about 0.5:1 v/v, about 0.75:1 v/v, about 1:1v/v, about 1:1.5 v/v, about 1:2 v/v, or about 1:4. The yield of compound(I) chloride salt free base is suitably greater than 90%.

The compound (I) chloride Type A salts provide for improved dissolutionat pH 4 to 5 as compared to compound (I) free base. At least 50 percentby weight of the mesylate salt dissolves in a pH 4.5 aqueous medium at37° C. in 10 minutes and at least 80 percent by weight of the mesylatesalt dissolves in the pH 4.5 aqueous medium at 37° C. in 30 minutes.

In certain aspects, the compound (I) chloride salt form provided hereinis essentially pure. For instance, in various aspects, the crystallinechloride salt purity is of at least about 90%, at least about 95%, atleast about 97%, at least about 98%, at least about 99%, at least about99.2%, at least about 99.5%, at least about 99.6%, at least about 99.7%or at least about 99.8% by weight of a single crystalline form, theremainder of the total weight which may be other crystalline oramorphous forms and/or other compounds. In some aspects, the equivalentratio of compound (I) to chlorine anion is about 1:1. In one aspect, thecrystalline chloride salt is essentially a single-component crystallineform or a single polymorph. In aspects, the crystalline form isessentially free of an amorphous form of compound (I). In certainaspects, the crystalline compound (I) chloride salt has an XRPD patternessentially as provided in FIG. 28 and/or FIG. 29. In some aspects, thecrystalline chloride salt has an XRPD pattern comprising one or morepeaks (e.g., at least three, at least four, at least five, at least six,or at least seven peaks) selected from peaks with 2θ angle degrees±0.22θ angle degrees of about 3.97, about 6.83, about 7.92, about 10.46,about 11.87, about 14.21, about 15.79 and about 19.76.

In some aspects, compound (I) sulfate salts are provided. In someaspects, compound (I) sulfate salt Form A is generally prepared by aprocess comprising: (i) forming a solution of compound (I) free baseForm A in a suitable solvent, (ii) combining the solution with astoichiometric excess of sulfuric acid to form compound (I) sulfate saltin solution, (iii) formation of compound (I) sulfate salt Form A bycrystallization, (iv) isolation of crystallized compound (I) sulfatesalt Form A, (v) optionally washing of the isolated compound (I) sulfatesalt Form A, and (vi) drying. Suitable solvents include polar proticsolvents and polar aprotic solvents as described elsewhere herein. Insome aspects, the solvent for compound (I) free base dissolution is DCMand crystallization is done in a solvent system comprising DCM and ACN.The compound (I) free base concentration in the solvent is suitablyabout 0.05 mmol/mL, about 0.1 mmol/mL, about 0.15 mmol/mL, about 0.2mmol/mL, about 0.25 mmol/mL, about 0.3 mmol/mL, about 0.4 mmol/mL, about0.5 mmol/mL, about 0.6 mmol/mL, or about 0.7 mmol/mL. The dissolutiontemperature is suitably about 15° C., about 20° C., about 25° C., about30° C., about 35° C., about 40° C., about 45° C., about 50° C., about55° C., about 60° C., about 65° C., or about 70° C. In some aspects,dissolution is done at from about 15° C. to about 30° C. (roomtemperature). H₂SO₄ is added in a stoichiometric amount for thepreparation of the mono-sulfate salt, and the mole ratio of compound (I)free base to H₂SO₄ is suitably about 1:1.01, about 1:1.05, about 1:1.1,about 1:1.15, or about 1:1.2. The H₂SO₄ is suitably about 0.1 M, about0.20 M, about 0.3 M or about 0.4 M. In some aspects, the H₂SO₄ isprepared by diluting concentrated H2SO4 with the solvent used todissolve compound (I) free base (e.g., DCM). In some aspects, afterH₂SO₄ addition, the solution comprising compound (I) sulfate is heatedto greater than 30° C., such as to about 35° C. or about 40° C.whereupon the solution is seeded with compound (I) sulfate salt Form Acrystals to form a slurry. Seed crystal amount is suitably about 1 wt.%, about 3 wt. %, about 5 wt. %, about 10 wt. % based on the amount ofcompound (I) free base. In some aspects, prior to seed crystal addition,a first portion of an anti-solvent may be added to the compound (I)sulfate solution. In some such aspects, the anti-solvent is ACN and theamount of compound (I) sulfate solution to anti-solvent is about 1:1v/v, about 1.5:1 v/v, about 2:1 v/v, about 2.5:1 v/v or about 3:1 v/v.After seed addition, anti-solvent is added to the slurry over a timeperiod of about 1 hour, about 6 hours, about 12 hours or about 18 hours.The amount of compound (I) sulfate solution to anti-solvent is about 1:2v/v, about 1:3 v/v, about 1:4 v/v, about 1:5 v/v, about 1:6 v/v, about1:7 v/v, about 1:8 v/v, about 1:9 v/v, or about 1:10 v/v. Afteranti-solvent addition, the slurry is cooled to less than 30° C., such asabout 25° C., about 20° C., about 15° C., about 10° C., or about 5° C.over a time period of about 0.5 hours, about 1 hour, about 2 hours,about 3 hours, about 4 hours, about 5 hours or about 6 hours, or more,and held at temperature for about 1 hour, about 2 hours, about 3 hours,about 4 hours, about 5 hours, about 6 hours, or more. Compound (I)sulfate salt Form A crystals may be suitably isolated and collected bysolid-liquid separation techniques known in the art such as filtrationand centrifugation. The collected crystals may be dried by techniquesknown in the art, such as vacuum drying at a temperature of less thanabout 60° C. The yield of compound (I) sulfate salt free base issuitably greater than 90%.

In certain aspects, the compound (I) sulfate salt form provided hereinis essentially pure. For instance, in various aspects, the crystallinesulfate salt purity is of at least about 90%, at least about 95%, atleast about 97%, at least about 98%, at least about 99%, at least about99.2%, at least about 99.5%, at least about 99.6%, at least about 99.7%or at least about 99.8% by weight of a single crystalline form, theremainder of the total weight which may be other crystalline oramorphous forms and/or other compounds. In some aspects, the equivalentratio of compound (I) to sulfate anion is about 1:1. In one aspect, thecrystalline compound (I) sulfate salt is essentially a single-componentcrystalline form or a single polymorph. In aspects, the crystalline formis essentially free of an amorphous form of compound (I). In certainaspects, the crystalline compound (I) sulfate salt has an XRPD patternessentially as provided in FIG. 30. In some aspects, the crystallinesulfate salt has an XRPD pattern comprising one or more peaks (e.g., atleast three, at least four, at least five, at least six, or at leastseven peaks) selected from peaks with 2θ angle degrees±0.2 2θ angledegrees of about 3.72, about 5.17, about 10.34, about 11.53, about13.76, about 14.71, about 15.06, about 16.29, about 18.28 and about19.74. In some aspects, the crystalline compound (I) sulfate saltexhibits three endothermal peaks on DSC between room temperature andabout 300° C., where a first endothermal peak occurs between about 130°C. to about 145° C., between about 136° C. to about 140° C., or fromabout 137° C. to about 139° C.; where a second endothermal peak occursat between about 210° C. to about 225° C., between about 214° C. toabout 219° C. from, or from about 216° C. to about 218° C.; and whereina third endothermal peak occurs at between about 265° C. to about 280°C., between about 270° C. to about 275° C., or from about 271° C. toabout 273° C.

Methods of Treatment

The dosage form compositions of the present disclosure are useful fortreating a human or animal patient suffering from a disease or disorderarising from abnormal cell growth, function or behavior associated withBtk kinase such as immune disorders, cancer, cardiovascular disease,viral infection, inflammation, metabolism/endocrine function disorders.Patients suffering from such a disease or disorder may thus be treatedby a method comprising the administration thereto of a therapeuticamount of a dosage form composition of the present disclosure. Thecondition of the patient may thereby be improved or ameliorated.

The dosage form compositions of the present disclosure may be dosed andadministered in amounts, concentrations, schedules, course, vehicles androute of administration, consistent with good medical practice. Factorsfor consideration in this context include the particular disorder beingtreated, the particular mammal being treated, the clinical condition ofthe individual patient, the cause of the disorder, the site of deliveryof the agent, the method of administration, the scheduling ofadministration, and other factors known to medical practitioners. The“therapeutically effective amount” of the compound to be administeredwill be governed by such considerations, and is the minimum amountnecessary to ameliorate, or treat the indicated disorder. In general, Asa general proposition, the initial pharmaceutically effective amount ofcompound (I) is in the range of from about 0.1 mg/kg/day to about 100mg/kg/day, from about 0.5 mg/kg/day to about 20 mg/kg/day, or from about1 mg/kg/day to about 10 mg/kg/day on the basis of patient body weight.

The dosage form compositions of the present disclosure are useful fortreating diseases or conditions as arthritic diseases, such asrheumatoid arthritis, monoarticular arthritis, osteoarthritis, goutyarthritis, spondylitis; Behcet disease; sepsis, septic shock, endotoxicshock, gram negative sepsis, gram positive sepsis, and toxic shocksyndrome; multiple organ injury syndrome secondary to septicemia,trauma, or hemorrhage; ophthalmic disorders such as allergicconjunctivitis, vernal conjunctivitis, uveitis, and thyroid-associatedophthalmopathy; eosinophilic granuloma; pulmonary or respiratorydisorders such as asthma, chronic bronchitis, allergic rhinitis, ARDS,chronic pulmonary inflammatory disease (e.g., chronic obstructivepulmonary disease), silicosis, pulmonary sarcoidosis, pleurisy,alveolitis, vasculitis, emphysema, pneumonia, bronchiectasis, andpulmonary oxygen toxicity; reperfusion injury of the myocardium, brain,or extremities; fibrosis such as cystic fibrosis; keloid formation orscar tissue formation; atherosclerosis; autoimmune diseases, such assystemic lupus erythematosus (SLE), autoimmune thyroiditis, multiplesclerosis, some forms of diabetes, and Reynaud's syndrome; andtransplant rejection disorders such as GVHD and allograft rejection;chronic glomerulonephritis; inflammatory bowel diseases such as chronicinflammatory bowel disease (CIBD), Crohn's disease, ulcerative colitis,and necrotizing enterocolitis; inflammatory dermatoses such as contactdermatitis, atopic dermatitis, psoriasis, or urticaria; fever andmyalgias due to infection; central or peripheral nervous systeminflammatory disorders such as meningitis, encephalitis, and brain orspinal cord injury due to minor trauma; Sjogren's syndrome; diseasesinvolving leukocyte diapedesis; alcoholic hepatitis; bacterialpneumonia; antigen-antibody complex mediated diseases; hypovolemicshock; Type I diabetes mellitus; acute and delayed hypersensitivity;disease states due to leukocyte dyscrasia and metastasis; thermalinjury; granulocyte transfusion-associated syndromes; andcytokine-induced toxicity.

In some aspects, the treatable diseases or conditions are systemic andlocal inflammation, arthritis, inflammation related to immunesuppression, organ transplant rejection, allergies, ulcerative colitis,Crohn's disease, dermatitis, asthma, systemic lupus erythematosus, lupusnephritis, Sjogren's Syndrome, multiple sclerosis, scleroderma/systemicsclerosis, idiopathic thrombocytopenic purpura (ITP), anti-neutrophilcytoplasmic antibodies (ANCA) vasculitis, chronic obstructive pulmonarydisease (COPD) and psoriasis. In some particular aspects, the disease orcondition is selected from rheumatoid arthritis, systemic lupuserythematosus, and lupus nephritis.

The dosage form compositions of the present disclosure are also usefulfor treating cancer selected from breast, ovary, cervix, prostate,testis, genitourinary tract, esophagus, larynx, glioblastoma,neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoidcarcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC),small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma,pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, pancreatic, myeloid disorders, lymphoma, hairy cells, buccalcavity, naso-pharyngeal, pharynx, lip, tongue, mouth, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system,Hodgkin's, leukemia, bronchus, thyroid, liver and intrahepatic bileduct, hepatocellular, gastric, glioma/glioblastoma, endometrial,melanoma, kidney and renal pelvis, urinary bladder, uterine corpus,uterine cervix, multiple myeloma, acute myelogenous leukemia, chronicmyelogenous leukemia, lymphocytic leukemia, chronic lymphoid leukemia(CLL), myeloid leukemia, oral cavity and pharynx, non-Hodgkin lymphoma,melanoma, and villous colon adenoma.

In some aspects of the disclosure, an article of manufacture, or “kit”,comprising a container containing a dosage form composition of thepresent disclosure useful for the treatment of the diseases anddisorders described above is provided. The kit may further comprise alabel or package insert on or associated with the container. The term“package insert” is used to refer to instructions customarily includedin commercial packages of therapeutic products, that contain informationabout the indications, usage, dosage, administration, contraindicationsand/or warnings concerning the use of such therapeutic products.Suitable containers include, for example, bottles, blister packs, etc.The container may be formed from a variety of materials such as glass orplastic. The label or package insert indicates that the dosage formcomposition is used for treating the condition of choice, such asrheumatoid arthritis, systemic lupus erythematosus, or lupus nephritis.The label or package insert may also indicate that the dosage formcomposition can be used to treat other disorders.

The kit may further comprise directions for the administration of thedosage form compositions of the present disclosure and, if present, asecond pharmaceutical formulation as described elsewhere herein. Forexample, the kit may further comprise directions for the simultaneous,sequential or separate administration of the first and secondpharmaceutical compositions to a patient in need thereof.

In another aspect, kits may provide a number of unit dosages. Such kitscan include a card having the dosages oriented in the order of theirintended use. An example of such a kit is a “blister pack”. Blisterpacks are well known in the packaging industry and are widely used forpackaging pharmaceutical unit dosage forms. If desired, a memory aid canbe provided, for example in the form of numbers, letters, or othermarkings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

Combination Therapy and Kits

The dosage form compositions of the present disclosure may be employedalone or in combination with an additional therapeutic agent for thetreatment of a disease or disorder described herein, such asinflammation or a hyperproliferative disorder (e.g., cancer). Theadditional therapeutic may be an anti-inflammatory agent, animmunomodulatory agent, chemotherapeutic agent, an apoptosis-enhancer, aneurotropic factor, an agent for treating cardiovascular disease, anagent for treating liver disease, an anti-viral agent, an agent fortreating blood disorders, an agent for treating diabetes, and an agentfor treating immunodeficiency disorders. The second therapeutic agentmay be an NSAID anti-inflammatory agent. The second therapeutic agentmay be a chemotherapeutic agent. The second compound of thepharmaceutical combination formulation or dosing regimen preferably hascomplementary activities to the compound (I) such that they do notadversely affect each other. Such compounds are suitably present incombination in amounts that are effective for the purpose intended.

The combination therapy may be administered in a simultaneous or in asequential regimen. When administered sequentially, the combination maybe dosed in two or more administrations. The combined administrationincludes co-administration, using separate formulations or a singlepharmaceutical formulation, and consecutive administration in eitherorder, wherein preferably there is a time period while both (or all)active agents simultaneously exert their biological activities. Suitabledosages for any of the above co-administered agents are those presentlyused and may be lowered due to the combined action (synergy) of theadditional therapeutic agents.

The combination therapy may be synergistic such that the effect achievedwhen the active ingredients used together is greater than the sum of theeffects that results from using the compounds separately. A synergisticeffect may be attained when the active ingredients are: (1) administeredor delivered simultaneously; (2) administered in alternation or inparallel; or (3) by some other regimen. When delivered in alternationtherapy, a synergistic effect may be attained when the compounds areadministered or delivered sequentially. In general, during alternationtherapy, an effective dosage of each active ingredient is administeredsequentially, i.e., serially, whereas in combination therapy, effectivedosages of two or more active ingredients are administered together.

In combination therapy, a kit may comprise (a) a first container with adosage form composition of the present disclosure and, optionally, (b) asecond container with a second pharmaceutical formulation containedtherein for co-administration with the dosage form compositions of thepresent disclosure. In such aspects, the kit may comprise a containerfor containing the separate compositions such as a divided bottle or adivided foil packet, however, the separate compositions may also becontained within a single, undivided container. Typically, the kitcomprises directions for the administration of the separate components.The kit form is particularly advantageous when the separate componentsare preferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

EXAMPLES

Unless otherwise noted, in vitro analysis of stomach and small intestinedissolution was done in a two stage apparatus. In the first stage, afirst stirred vessel was used to simulate dissolution in the stomach.Stomach dissolution is suitably be measured at 37° C. at normal pH(about pH 1), achlorohydric stomach pH (in the range of from about 4 toabout 6), or at an intermediate pH by selection of 500 mL of a mediumhaving a desired pH, such as 1 or 4.5, and with typical sampling timesof 5, 15 and 25 minutes. After a 30 minute dissolution time, thecontents were transferred to a second stage stirred vessel used tosimulate the small intestine that contained 1000 mL of a Fasted-StateSimulated Intestinal Fluid (FaSSIF) buffer at 37° C. having a pH of 6.5with typical sampling times of 35, 45, 60, 90, 120, 180 and 240 minutes.

Unless otherwise noted, the XRPD patterns were acquired on a PANalyticalEmpyrean diffractometer (Almelo, The Netherlands). Samples were gentlyflattened onto a zero-background silicon insert sample holder. Acontinuous 20 scan range of 3° to 400 was used with a Cu Kα (λ 1.54056Å) radiation source and a generator power of 45 kV and 40 mA. A 20 stepsize of 0.0167 degrees/step with a step time of 17.780 second/step wasused. Experiments were performed at room temperature and at ambienthumidity.

Unless otherwise noted, DSC thermograms were acquired using a TAInstruments Q2000/Q200 Differential Scanning calorimeter (New Castle,Del., USA). The sample was weighed out directly into an aluminum DSCpan. The closed pan configuration was used. Unless otherwise noted, thetemperature was ramped from 25° C. to 300° C. at the rate of 10° C./min.

Unless otherwise noted, TGA thermograms were acquired using a TAInstruments Q5000/Q500 Thermogravimetric Analyzer (New Castle, Del.,USA). Samples were weighed out into the pan. Unless otherwise noted, thetemperature was ramped from room temperature to 300° C. at the rate of10° C./min.

Unless otherwise noted, DVS were acquired using standard procedures on aDVS Intrinsic 1 type from Surface Measurement Systems Ltd. (Alperton,Middlesex, UK). The standard isotherm run is a cycle starting atrelative humidity (“RH”) 0% to RH 95% at 10% intervals, followed bydrying to RH 0% in 10% RH intervals (5% interval between RH 90% and95%).

Example 1: Compound (I) Mesylate Crystalline Polymorph Type A

Compound (I) free base starting material was prepared as described inU.S. Pat. No. 8,716,274 B2. Compound (I) starting material wascharacterized by XRPD against a Compound (I) free base Type A standard.The XRPD results are presented in FIG. 1 and show that the starting freebase material is Type A and conforms to the compound (I) free base TypeA standard. TGA and DSC data are presented in FIG. 2. The TGA data showsa weight loss of up to 0.9% up to 250° C. and a sharp melting endothermwith 278.6° C. with an onset at 276.4° C.

In a first experiment for preparing compound (I) mesylate salt polymorphA, 100 mg (about 0.15 mmol) of compound (I) free base Type A wascombined with 15.7 mg (about 0.16 mmol) methanesulfonic acid in a 5 mLvial. 1 mL of ethanol was added to the vial and was stirred (750 rpm,magnetically) at 50° C. to obtain a clear solution. The solution wascooled to 40° C. and held at 40° C. for 10 minutes. About 3 mg ofcompound (I) mesylate salt type A was added and the admixture was heldat 40° C. for 60 minutes. The mixture was cooled to 20° C. at a rate of0.1° C./minute and held at 20° C. for 10 hours. The solids were thenisolated by centrifugation at 10,000 rpm and were then dried undervacuum at room temperature. The dried solids were collected to yield106.9 mg of compound (I) mesylate polymorph type A for a yield of 93.4%.The XRPD pattern for the prepared compound (I) mesylate type A ascompared to compound (I) mesylate type A standard is presented in FIG.3. XRPD peak data for compound (I) free base Type A is recited in Table1.

TABLE 1 Compound (I) Free Base Type A XRPD data Pos. Height FWHM Leftd-spacing Rel. Int. [° 2Th.] [cts] [° 2Th.] [Å] [%] 3.521 2654.2040.0640 25.097 100.00 10.402 437.958 0.0896 8.505 16.50 11.897 529.7050.0768 7.439 19.96 12.321 546.315 0.0768 7.184 20.58 13.900 308.8700.0895 6.371 11.64 15.158 510.903 0.1023 5.845 19.25 15.978 600.5660.0895 5.547 22.63 16.757 423.526 0.0768 5.291 15.96 17.368 340.2680.0895 5.106 12.82 17.878 60.536 0.2047 4.961 2.28 18.920 774.691 0.11514.691 29.19 19.751 99.957 0.1023 4.495 3.77 20.557 163.682 0.1023 4.3216.17 20.814 171.119 0.1023 4.268 6.45 21.490 605.213 0.1151 4.135 22.8021.998 278.325 0.1279 4.041 10.49 23.644 92.851 0.1023 3.763 3.50

In a second experiment for preparing compound (I) mesylate saltpolymorph A, an acid stock solution of methanesulfonic acid in ethanolwas prepared by adding 3.037 g (about 31.6 mmol) of methanesulfonic acidto 100 mL ethanol and vortexing. The acid stock solution was stored atroom temperature until use. Compound (I) free base type A (20.0 g, about30.1 mmol) was combined with 100 mL ethanol in a 500 mL three-neckedjacketed crystallizer with a 2-flight overhead anchor-type agitator andwas stirred at 50° C. at 350 rpm. The acid stock solution was admixedwith the contents of the crystallizer within 20 minutes to yield a brownsolution. The solution was cooled to 40° C. and held at 40° C. for 20minutes. Compound (I) mesylsate type A seed crystals (0.2 g) were addedto the solution. The seed crystals were dissolved after 10 minutes. Thesolution was further cooled to 35° C. and held at 35° C. for 30 minutes.Compound (I) mesyl sate type A seed crystals (0.8 g) were added to thesolution whereupon the solution became cloudy. The admixture was held at35° C. for 1 hour. Within 12 hours, 100 mL of n-heptane was charged tothe crystallizer and thereafter held at 35° C. for 2 hours. The mixturewas then cooled to 20° C. and held at 20° C. for 3 hours. The contentsof the crystallizer were collected by filtration and dried at 40° C. for15 hours. The process yielded 24.0 g of compound (I) mesylate type Asolids with a yield of 92.8%.

The product after drying contained at 5.9% residual ethanol, possiblydue to the channel structure nature that depressed the effectiveness ofvacuum drying. Considering the observed properties of the proposedchannel structure, storing experiments at different humid atmosphereswere set up to evaluate the possibility for replacing ethanol withwater. As summarized in Table 2 below, after exposure at ambientconditions (RT/26% RH) and RT/57% RH (controlled by NaBr saturatedaqueous solution) for 24 hrs, significant decrease of both ethanol andn-heptane was observed, indicating that wet drying, at RT/(from about25% RH to about 55% RH), may be effective for ethanol removal. In Table2, “TGA” refers to thermographic analysis, “KF” refers to Karl Fisher,“EtOH” refers to ethanol with results reported in ppm, and “n-Hep”refers to n-heptane with results reported in ppm, “Moist” refers tomoisture.

TABLE 2 Residual Sample Solvents Wt loss Moist ID Description Scale EtOHn-Hep (TGA) (KF) 1 Initial Mesylate 24 g 58,644 719 7.6% N/A (vacuumdrying at 40° C. for 15 hrs) 2 Mesylate exposed at 23 g 1101 1.4 9.3%9.6% RT/26% RH for 24 hrs) 3 Mesylate exposed at 0.1 g 146 6.8 N/A N/ART/57% RH for 24 hrs)

The compound (I) mesylate type A product was analyzed by DVS with theresults reported in FIG. 4. Without being bound to any particulartheory, as shown in FIG. 4, the bump observed at 25° C./80% RH may havebeen caused by the replacement of residual organic solvent with water.XRPD results for the product before and after DVS are presented in FIG.5 where no significant solid form change was observed. Without beingbound to any particular theory, it is believed that the XRPD results ofFIG. 5 indicate a likely channel structure for the compound (I)mesylsate type A product.

The compound (I) mesylate type A product was analyzed and the resultsare reported in Table 3 where “PLM” refers to polarized lightmicroscopy; “XRPD” refers to X-ray powder diffractometry; “NMR” refersto nuclear magnetic resonance; “HPLC” refers to high pressure liquidchromatography; and “GC” refers to gas chromatography. In additionaldetail, a needle-like product was obtained that conformed to mesylateType A, as per the XRPD pattern comparison in FIG. 6. TGA data showed aweight loss of 9.3% up to 140° C., and two endotherms at 117.4° C. and216.9° C. (peak temperature) were observed in DSC (FIG. 7). ¹H NMRresults in FIG. 8 indicate a stoichiometry of 1.00 for the re-preparedcompound (I) mesylate Type A. XRPD peak data for compound (I) mesylatesalt Type A is recited in Table 4.

TABLE 3 Test Results Appearance Beige powder Morphology by PLMAgglomeration with fine crystals Crystal form by XRPD Compound (I)mesylate type A Weight loss by TGA (%) 9.3 (to 140° C.) Endotherm by DSC(peak, ° C.) 117.4, 216.9 Stoichiometric ratio by ¹H NMR 1.00 Watercontent by KF (%) 9.6 HPLC Purity (area %) 100.0 Residual solvent by GC(ppm) EtOH: 1101.5; n-heptane: 1.4

TABLE 4 Compound (I) Mesylate Salt Type A XRPD data Pos. Height FWHMLeft d-spacing Rel. Int. [° 2Th.] [cts] [° 2Th.] [Å] [%] 3.784 450.1220.1535 23.348 68.01 6.483 510.820 0.06400 13.634 77.18 7.907 91.0770.1535 11.182 13.76 9.918 661.835 0.06400 8.918 100.00 11.894 193.6260.1023 7.441 29.26 14.263 257.280 0.06400 6.210 38.87 15.116 107.1820.1535 5.861 16.19 15.885 398.986 0.07675 5.579 60.28 17.236 39.5880.5117 5.145 5.98 18.100 96.738 0.2047 4.901 14.62 19.865 82.458 0.15354.470 12.46 20.549 173.055 0.1023 4.322 26.15 21.411 94.411 0.1023 4.15014.27

The dissolution of 100 mg compound (I) mesylate salt was evaluated in 2mL pH 4.5 aqueous media at 37° C. over time as compared to thedissolution of 100 mg compound (I) free base in 2 mL of the buffer. Theresults are presented in Table 5 below wherein the pH of the mediacomprising dissolved compound (I) mesylate salt was 4.3 and the pH ofthe media comprising dissolved compound (I) free base was 4.8.

TABLE 5 Time Compound (I) mesylate salt Compound (I) free base (min) (%dissolved) (% dissolved) 15 81.4 0 30 94.5 0.5 45 98.2 2.3 60 98.2 4.1

Example 2: Dissolution of Compound (I) Free Base Versus pH

The solubility of compound (I) free base was evaluated in buffers ofvarying pH including Fed State Simulated Intestinal Fluid (“FeSSIF”) (pH5) and Fasted State Simulated Intestinal Fluid (“FaSSIF”) (pH 6.8). Theresults are reported in Table 6 below.

TABLE 6 pH Solubility (mg/mL) 2.54 35.9 2.60 6.48 3.02 1.66 3.80 0.0365.04 0.001 6.06 0 6.94 0.001 7.76 0.001 FeSSIF (pH 5)   0.018 FaSSIF (pH6.8) 0.013

Example 3: Effect of Acid on Compound (I) Free Base Dissolution

In a first experiment, fumaric acid, succinic acid, citric acid andfumaric acid were evaluated for the capability to dissolve compound (I)free base in a 0.0000316N HCl buffer having a pH of 4.5 (representativeof an achlorohydric stomach) as compared the free base in the absence ofacid. In the trials, 3 tablets, each containing 100 mg compound (I) freebase (20 wt. %) combined with 150 mg acid (30 wt. %) were used, and thein vitro stomach and small intestine dissolution was evaluated in thetwo stage apparatus described elsewhere herein. The results arepresented in FIG. 9 wherein the indicated stomach pH indicates the pH atthe 25 minute sampling time and the small intestine pH indicates thesimulated intestinal pH at the 240 minute sampling time.

The effect of 10%, 20% and 30% fumaric acid content were evaluated forthe capability to dissolve compound (I) free base as compared to thefree base in the absence of fumaric acid in the system describedimmediately above. In the trials, 3 tablets, each containing 100 mgcompound (I) free base (20 wt. %) combined with 50 mg acid (10 wt. %),100 mg acid (20 wt. %), and 150 mg acid (30 wt. %) were used, and the invitro stomach and small intestine dissolution was evaluated in the twostage apparatus described elsewhere herein. The results are presented inFIG. 10 wherein the indicated stomach pH indicates the pH at the 25minute sampling time and the small intestine pH indicates the simulatedintestinal pH at the 240 minute sampling time.

Example 4: Dissolution of Tablets Comprising Compound (I) Free Base andFumaric Acid

Tablets of the composition disclosed in Table 7 below were preparedwherein “API” refers to the active pharmaceutical ingredient compound(I) free base, “FA” refers to fumaric acid, “MCC” refers tomicrocrystalline cellulose, “Cros-Na” refers to croscarmellose sodium,“SiO₂” refers to colloidal silicon dioxide, “Mg stearate” refers tomagnesium stearate, and where all amount are reported in wt. %. In vitroanalysis of stomach and small intestine dissolution was done in the twostage apparatus described elsewhere herein wherein a 4.5 pH stomach pHwas simulated. Samples were evaluated at the indicated time for compound(I) concentration in solution. The results are presented in FIG. 11.

TABLE 7 Mg Tablet API FA MCC Lactose Cros-Na SiO₂ Stearate DCT-1 15%  0%68.06% 11.44%   3% 1%  1.5% ACT-8 15% 10% 59.5% 10% 3% 1%  1.5% ACT-915% 15% 64.75%  0% 3% 1% 1.25% ACT-11 15%  5% 54.75% 20% 3% 1% 1.25%

Example 5: Amorphous Solid Dispersions Comprising Compound (I) Free Baseand at Least One Polymer

Various amorphous solid dispersions comprising compound (I) free baseand at least one polymer were prepared by spray drying 10 g (solidsbasis) spray solutions comprising 10 wt. % solids in a 90:10 acetone towater (w/w). For ASD formulations 7 to 14: the compound (I) free basecontent (“API”) was 20 wt. %; the atomization pressure was 24 psi; andthe drying gas flow rate was 43 kg/hr. For ASD formulations 32 to 35, 41and 42: the atomization pressure varied from 24 to 32 psi; the dryinggas flow rate was 43 kg/hr; the API content was 20 wt. % (ASD #s 32, 33,35 and 41), 30 wt. % (ASD #42), or 50 wt. % (ASD #34). For ASDformulations 56 to 63: the API content was 50 wt. %; the atomizationpressure was 30 psi; and the drying gas flow rate was 43 kg/hr. The ASDformulations and spray drying parameters are disclosed in Table 8 below.“ASD” refers to the amorphous solid dispersion composition referencenumber, “API:poly” refers to the ratio of crystalline compound (I) freebase to polymer (1) or the ratio of crystalline compound (I) free baseto polymer (1) and to polymer (2). “Flow” refers to solution flow ratein mL/min. “T_(in)” refers to the inlet temperature in ° C. “T_(out)”refers to the outlet temperature in ° C. “Tg” refers to the glasstransition temperature in ° C. The copovidone used was Kollidon VA64 andthe PVP used was Kollidon 17PF.

TABLE 8 ASD Polymer (1) Polymer (2) API:Poly Flow T_(in) T_(out) T_(g)1T_(g)2  7 Soluplus ® — 20:80 30 95 48 87.2 —  8 Copovidone — 20:80 30 9649 118.3 —  9 HPMC E3 — 20:80 26 94 48 137.2 — 10 HPMCAS-L — 20:80 30 9349 126.8 — 11 HPMCAS-L PEG 400 20:78:2  28 95 50 111.2 — 12 Kollidon17PF — 20:80 26 115 48 146.2 — 13 Eudragit E100 — 20:80 30 96 51 67.3 —14 Eudragit E100 PEG 400 20:78:2  26 95 50 53.5 — 32 Eudragit E100Copovidone 20:40:40 25 81 37 63.1 121.8 33 Eudragit E100 PVP 20:40:40 25112 36 65.7 151.2 34 Eudragit E100 — 50:50 25 86 36 72.6 153.4 35Eudragit E100 — 20:80 25 69 38 65.8 N/A 41* Eudragit E100 — 20:80 20 7736 87.9 — 42 Eudragit E100 — 30:70 25 80 36 63.6 — 56 HPMCAS-L — 50:5015 115 47 131.9 — 57* HPMCAS-L — 50:50 15 115 47 119.4 — 58* HPMC —50:50 15 115 48 150.6 — 59 HPMC — 50:50 15 115 48 138.2 — 60 Copovidone— 50:50 15 115 45 124.7 — 61 PVP — 50:50 15 130 40 147.3 — 62*Copovidone — 50:50 15 115 46 135.3 — 63* PVP — 50:50 15 130 52 162.6 —*ASD formulations 41, 57, 58, 62 and 63 additionally contained 3 molarequivalents of HCl in the spray solution.

T_(g) analysis was done by modulated differential scanning calorimetrywith the following parameters: (1) Instrument: TA Q-2000, RCS90 chiller;(2) Temperature range: 0-200° C.; (3) Heating rate: 5° C./min; and (4)Modulation: ±2° C./20 sec. Each of ASD formulations 7 to 14, 41, 42 and56 to 63 exhibited a single Tg with no crystalline peaks below theT_(g), consistent with the formation of an intimately mixed amorphoussolid dispersion. ASD formulations 32 to 34 had a similar T_(g) in therange of 63 to 73° C. consistent with Eudragit E100 at 20% drug loading;however these mixtures with PVP-based polymers, as well as the higherdrug loading formulation showed a second T_(g) value possiblyindicating, without being bound to any particular theory, that the ASDpolymers are phase-separated or the dispersion formed non-homogenousdomains (i.e. regions either rich or poor in API or either of the twopolymers, in the case of ternary dispersions). Under one theory, andwithout being bound to any particular theory, this could indicate thatthe API is segregating to Eudragit rich domains with low T_(g).

Compound (I) free base and the ASD formulations were analyzed by x-raydiffraction with the following parameters: (1) Instrument: Bruker D2Phaser; (2) Scan mode: Coupled 2θ−θ; (3) Scan time: 1 sec; (4) 2θ range:1° to 40°; (5) Increment: 0.01°; (6) Voltage: 30 kV; (7) Current: 10 mA;(8) Rotation: 15 r/min; (9) Holder type: Cup; (10) Divergence slitwidth: 1.0 mm; and (11) Knife-edge width: 1.0 mm. XRD analysis indicatedthat the compound (I) free base appeared to be crystalline and each ASDformulation appeared to be amorphous with no evidence of crystallinepeaks.

The dissolution performance of unformulated compound (I) free base andASD formulations was assessed via a two-stage dissolution assay whichmeasured kinetic solubility in vitro over 210 minutes. The assay wasperformed in a modified USP II apparatus (paddles). The experimentmeasured the total drug dissolved in the presence of excess solid API(non-sink conditions), which included a combination of ‘free’ andcolloidal or polymer-bound drug in solution. In some evaluations—tosimulate the relatively high pH gastric environment in patients takingproton pump inhibitors—different simulated gastric media were used tobegin the two-stage experiment: either pH 1 (HCl buffer) or pH 4 or 5(acetate buffers) at a nominal compound (I) concentration of 2.0 mg/mL.In some other experiments, acetate buffer was replaced with a dilute HClsolution at similar pH, to better mimic the expected in vivoenvironment. After 30 minutes, the test material was transferred tofasted-state simulated intestinal fluid (FaSSIF) media consisting ofphysiologically relevant bile salts (SIF Powder, Biorelevant Inc.) in100 mM phosphate buffer, and the compound (I) concentration was dilutedto 1.0 mg/mL. pH of the phosphate buffer was adjusted as needed toobtain a simulated intestinal pH of 6.8±0.1 in the second stage of thedissolution experiment. The test material was sampled periodicallythroughout the test and samples were centrifuged at 13,000 r/min. Thesupernatant was diluted 1:1 with sample diluent and the compound (I)concentration was measured by HPLC. Dissolution test parameters are asfollows: (1) Dissolution apparatus: Distek 2100C, miniature vessels (100mL); (2) Stir rate: 100 r/min; (3) Temperature: 37° C.; (4) Gastricmedia: pH 1 HCl, pH 4 acetate, or pH 5 acetate buffer; (5) Intestinalmedia: FaSSIF, pH 6.8; (6) Gastric transfer time: 30 min; (7) Totaltime: 210 min: and (8) Sample diluent 50:40:10 H₂O:ACN:MeOH.

Results of unformulated compound (I) free base dissolution at threegastric conditions indicate that the kinetic dissolution was greatest inpH 1 gastric media, where it was fully dissolved at the dosedconcentration of about 2000 ug/mL. Upon transfer to intestinal media,the test that began in the more acidic condition maintained the greatestsuper-saturation indicating that greater gastric dissolution leads toimproved intestinal dissolution, despite the intestinal pH being thesame across all experiments. Non-sink dissolution results for ASDformulations 7 to 14 are given in Table 9 below where C_(max) is in μMand AUC is in hr*μM. The formulations with the greatest increase inintestinal and gastric dissolution at pH 1 (i.e. normal patientpopulations) were those which included Eudragit E100, a cationiccopolymer based on dimethylaminoethyl methacrylate, butyl methacrylate,and methyl methacrylate, that is used as a protective tablet coating anddesigned to dissolve at gastric pH up to 5. Eudragit E100 formulationsalso gave the greatest increase in AUC (when considering total drug insolution) in the simulated intestinal portion of the experiment at allpH conditions. In all cases, solid dispersion formulations gave greaterintestinal AUC. FIGS. 12 to 14 show the ASD non-sink dissolution resultsfor each pH condition plotted over time.

TABLE 9 Total drug API Gastric Intestinal ASD# (wt. %) Polymer pHC_(max) AUC C_(max) AUC 13 20 Eudragit E100 1 1851 53787 843 74111 14 20Eudragit 1 1771 52729 739 64061 E100:PEG4000 7 20 Soluplus ® 1 165241116 403 63358 8 20 Copovidone 1 1978 55156 143 19319 9 20 HPMC-E3LV 11768 40439 136 15677 12 20 PVP 1 1926 57439 104 15628 11 20 HPMCAS- 11921 53132 95 15311 L:PEG4000 10 20 HPMCAS-L 1 1792 51332 102 15195 API100 — 1 2102 62463 97 13908 13 20 Eudragit E100 4 779 22312 247 35182 1420 Eudragit 4 746 21769 259 34673 E100:PEG4000 7 20 Soluplus ® 4 47110557 178 26853 8 20 Copovidone 4 1000 25602 114 18596 12 20 PVP 4 86822184 93 15338 10 20 HPMCAS-L 4 504 10510 110 14850 11 20 HPMCAS- 4 42010090 93 14848 L:PEG4000 9 20 HPMC-E3LV 4 722 19053 84 13721 API 100 — 4145 3673 45 5413 13 20 Eudragit E100 5 558 16231 174 20777 14 20Eudragit 5 888 21403 147 18846 E100:PEG4000 8 20 Copovidone 5 121 322098 16386 12 20 PVP 5 246 6275 95 15541 10 20 HPMCAS-L 5 193 4289 9914822 9 20 HPMC-E3LV 5 219 6366 90 14342 11 20 HPMCAS- 5 307 7764 9113950 L:PEG4000 7 20 Soluplus ® 5 134 3038 80 13635 API 100 — 5 50 127368 5996

Non-sink dissolution results for ASD formulations 32 to 35 are given inTable 10 below. Gastric AUC was similar for all ASD formulations in allpH conditions. Of the ASDs tested, 20:80 Compound (I):Eudragit E100 (ASD#32) showed the greatest intestinal AUC at all pH conditions.

TABLE 10 Total drug API Gastric Intestinal ASD# (wt. %) Polymer pHC_(max) AUC C_(max) AUC 32 20 Eudragit 1 2061 60765 235 31233E100:copovidone 33 20 Eudragit E100:PVP 1 1929 57711 206 27707 34 50Eudragit E100 1 1956 58152 159 19808 35 20 Eudragit E100 1 1961 56289718 62120 32 20 Eudragit 4 909 26937 185 23499 E100:copovidone 33 20Eudragit E100:PVP 4 877 23283 179 21724 34 50 Eudragit E100 4 1037 30687138 16238 35 20 Eudragit E100 4 823 23747 247 33163 32 20 Eudragit 5 2427230 144 22181 E100:copovidone 33 20 Eudragit E100:PVP 5 310 8869 14719365 34 50 Eudragit E100 5 285 8235 126 15778 35 20 Eudragit E100 5 46812341 195 23294

Non-sink dissolution results for ASD formulations 35, 41 and 42 and theunformulated API are given in Table 11 below where “Ace” refers toacetate buffer.

TABLE 11 Total drug API Gastric Intestinal ASD# (wt. %) Polymer pHC_(max) AUC C_(max) AUC 35 20 Eudragit E100 1 (HCl) 1851 53787 843 7411135 20 Eudragit E100 4 (HCl) N/A N/A N/A N/A 35 20 Eudragit E100 5 (HCl)N/A N/A N/A N/A 35 20 Eudragit E100 4 (Ace) 779 22312 247 35182 35 20Eudragit E100 5 (Ace) 558 16231 174 20777 41 20 Eudragit E100 + 1 (HCl)2042 57413 875 83743 HCl (3 eq) 41 20 Eudragit E100 + 4 (HCl) 238 6544124 20090 HCl (3 eq) 41 20 Eudragit E100 + 5 (HCl) 245 6735 122 19022HCl (3 eq) 41 20 Eudragit E100 + 4 (Ace) 967 28344 273 34655 HCl (3 eq)41 20 Eudragit E100 + 5 (Ace) 511 12238 205 32746 HCl (3 eq) 42 30Eudragit E100 1 (HCl) 2197 65333 260 38188 42 30 Eudragit E100 4 (HCl)65 1881 102 15594 42 30 Eudragit E100 5 (HCl) 52 1248 111 16322 42 30Eudragit E100 4 (Ace) 977 27960 168 25562 42 30 Eudragit E100 5 (Ace)323 8871 152 20040 API 100 — 1 (HCl) 2102 62463 97 13908 API 100 — 4(HCl) 182 5303 97 7537 API 100 — 5 (HCl) 32 890 18 2033 API 100 — 4(Ace) 145 3673 45 5413 API 100 — 5 (Ace) 50 1273 68 5996

The HCl salt formulation with Eudragit E100 showed the greatest in vitrosimulated intestinal AUC compared to unformulated API and to 20:80Compound (I):Eudragit E100, particularly at the highest gastric pHtested, indicating that this approach may prove useful to enhancedissolution. The 30:70 Compound (I):Eudragit E100 resulted in lowerintestinal AUC at all pH conditions than 20:80 Compound (I):EudragitE100 previously tested.

Non-sink dissolution results for ASD formulations 56 to 63 are presentedin FIGS. 15A, 15B, 16A and 16B. Non-sink dissolution was performed asdescribed previously, except an intermediate gastric pH of 4.5 (HCl) wasused in place of the previous separately tested pH 4 and 5 gastricconditions. FIGS. 15A (pH 1 gastric pH) and 16A (pH 4.5 gastric pH)depict the entire concentration range tested, and FIGS. 15B and 16B zoomin on the concentration range for the simulated intestinal phase of theexperiment (e.g. 350 ug/mL).

All ASD formulations provided a 3- to 4-fold enhanced sustainment ofdissolution following gastric transfer relative the crystalline API, andall four polymers performed equivalently within experimental variabilityfollowing gastric transfer. The results indicate that at 50% drugloading, it is believed that the dissolution of the amorphous drugitself, rather than any specific interaction with the polymers, thatdetermines dissolution performance. While initial dissolutionperformance in gastric pH appeared quite different depending on thepolymer used, all the curves converged to a similar equilibriumdissolution of about 100 ug/mL under intestinal pH conditions. Theaddition of HCl salt to the ASDs significantly enhanced dissolution atelevated gastric pH of 4.5, but the enhancement was not indicated at asimulated intestinal pH of 6.

ASD formulations 60 (50:50 API:Copovidone), 59 (50:50 API:HPMC) and 56(50:50 HPMCAS-L) were evaluated for short term stability. Two packagingconfigurations—Open and Closed—were used. For open packaging, 1 g of theASD formulation was placed in a 75 cc white HDPE bottle without cap, anda cotton ball placed in neck of bottle. For closed packaging, 1 g of theASD formulation was placed in a 4″×6″ LDPE bag (4 mil), goose-necked andclosed with a plastic cable tie. The bag placed in a 4″×6″ foil pouch,heat sealed with one 0.5 g silica desiccant packet between LDPE bag andfoil. The open and closed containers were stored at 40° C. and at 75%RH. Sampling time points were 2 weeks and 4 weeks.

The ASD formulations tested were off-white to light gray powders, theappearance of which was unchanged on storage for 4 weeks at acceleratedconditions. Some increase in clumping of powders was observed, but theseclumps were easily broken up to obtain a flowing powder. Potency andrelated substance were determined by HPLC as follows: (1) Column:AgilentPoroshell EC-C18 150×3.0 mm, 2.7 μm; (2) Mobile Phase A: 10 mMammonium formate (aq.) pH 3.7; (3) Mobile Phase B: 80:20acetonitrile:methanol; (4) Gradient: 0 min (10% mobile phase B), 2 min(45% mobile phase B), 10 min (50% mobile phase B), 15 min (75% mobilephase B), 18 min (95% mobile phase B), 20 min (95% mobile phase B), 20.1min (10% mobile phase B) and 30 min (10% mobile phase B); (5) ColumnTemperature: 40° C.; (6) Flow Rate: 0.5 mL/min; (7) Sample Temperature:RT; (8) Injection Volume: 10 μL; (9) Detection Method: UV; (10)Detection Wavelength: 245 nm; (11) Detection Bandwidth: 4 nm; (12) RunTime: 30 min; (13) Target Concentration: 0.20 mg/mL; and (14) Diluent:70:30 acetonitrile:water. The stability results are presented in Table12 where “Total Rel. Sub.” refers to total related substances.

TABLE 12 Total Rel. Sub. Water Potency (wt. %) (% peak area) (wt. %) ASD# Time 0 2 wks 4 wks Time 0 2 wks 4 wks 4 wks 56 Closed 48.1% 48.1%44.8% 0.52% 0.45% 0.75% 1.00 56 Open 43.8% 35.8% 1.14% 1.50% 4.01 59Closed 50.0% 51.5% 51.2% 0.08% 0.19% 0.14% 1.54 59 Open 47.4% 48.4%0.32% 0.27% 6.25 60 Closed 48.2% 49.4% 50.2% 0.08% 0.24% 0.14% 1.52 60Open 44.4% 46.5% 0.45% 0.81% 8.41

Example 6: Pharmacokinetic Evaluation of Compound (I) Free Base inCombination with Fumaric Acid in a Canine Model

The pharmacokinetics (“PK”) of Example 4 Tablets DCT-1 (comprising 15wt. % compound (I) free base and no fumaric acid), ACT-8 (comprising 15wt. % compound (I) free base and 10 wt. % fumaric acid), ACT-9(comprising 15 wt. % compound (I) free base and 15 wt. % fumaric acid)and ACT-11 (comprising 15 wt. % compound (I) free base and 5 wt. %fumaric acid) were evaluated in a canine pH dependent absorption model(see Zhou, R., et al., “pH-dependent dissolution in vitro and absorptionin vivo of weakly basic drugs: development of a canine model”, Pharm.Res. 2005 February; 22(2): 188-92), incorporated by reference herein inits entirety). In the study, 6 treatment groups consisting of 5 malebeagle dogs each were orally dosed according to the protocol outlined inTable 13 below where “API” refers to compound (I) free base, and “FA”refers to fumaric acid. Pentagastrin stimulates the secretion of gastricacid and was administered at 6 ag/kg by intramuscular injection at 30minutes (2 minutes) before tablet dosing. Famotidine inhibits thesecretion of gastric acid and was administered at 40 mg/dog by oraladministration at 180 minutes (±10 minutes) before tablet dosing.

TABLE 13 Group Tablet API:FA Target API Dose (mg) Pre-Treatment 1 DCT-1No FA 200 mg (2 tabs per dog) Pentagastrin 2 DCT-1 No FA 200 mg (2 tabsper dog) Famotidine 3 ACT-11 3:1 200 mg (2 tabs per dog) Famotidine 4ACT-8 1.5 200 mg (2 tabs per dog) Pentagastrin 5 ACT-8 1.5 200 mg (2tabs per dog) Famotidine 6 ACT-9 1:1 200 mg (2 tabs per dog) Famotidine

The results are presented below in Table 14 and in FIGS. 17 and 18 whereC_(max) in μM, AUC is in hr*μM, and “FA” refers to fumaric acid. In FIG.17, “G1” refers to Group 1, “G2” refers to Group 2, “G3” refers to Group3, “G4” refers to Group 4, “G5” refers to Group 5, and “G6” refers toGroup 6.

TABLE 14 % of P (com- Control pared to Group Treatment C_(max)AUC_(0-24 h) Group 1 group 2) 1 Pentagastrin, 7.14 ± 1.53 71.2 ± 1.53100%  <0.0001 no FA 2 Famotidine, 0.95 ± 1.3  8.39 ± 10.2 12% — no FA 3Famotidine, 1.91 ± 0.8   14 ± 9.71 20% >0.9999 5% FA 4 Famotidine, 2.62± 0.64 21.3 ± 6.45 30% 0.7858 10% FA 5 Famotidine, 4.62 ± 1.18 43.9 ±51.7 62% 0.0026 15% FA 6 Pentagastrin, 9.12 ± 0.65  106 ± 11.5 149% <0.0001 10% FA

The results indicate that increasing fumaric acid tablet concentrationresults in an apparent concentration-dependent increase in absorptionand exposure for dogs treated with famotidine.

Example 7: PK Evaluation of Compound (I) Free Base in Combination withFumaric Acid as Compared to Compound (I) Mesylate Salt in a Canine Model

The PK of tablets designated ACT-19 (comprising compound (I) free baseand fumaric acid) and MSY-1 (comprising compound (I) mesylate salt) wereevaluated in a canine model as described elsewhere herein. The tabletformulations are disclosed in Table 15 below wherein tablet MSY-1contained 15 wt. % compound (I) on a free base basis; “FA” refers tofumaric acid; “MCC” refers to microcrystalline cellulose; “Cros-Na”refers to croscarmellose sodium; “SiO₂” refers to colloidal silicondioxide; “Mg stearate” refers to magnesium stearate; “D1001” to “D1005”refers to individual dogs; and where all amount are reported in wt. %.Each dog was dosed at 200 mg compound (I) (free base basis) and wherephase 1 refers to dosing with ACT-19 tablets and wherein phase 2 refersto dosing with MSY-1 tablets.

TABLE 15 Lac- Cros- Mg Tablet Phase API FA MCC tose Na SiO₂ StearateACT-19 1   15% 15% 54.5% 10% 3% 1% 1.5% MSY-1 2 18.87%  0% 65.63% 10% 3%1% 1.5%

The time-concentration plasma concentration results in μM for phase 1(compound (I) free base+fumaric acid) and phase 2 (compound (I) mesylatesalt) are presented in Tables 16 to 19 below.

TABLE 16 Phase 1 (ACT-19 tablets) and Phase 2 (MSY-1 tablets) plasmaconcentration results C_(max) T_(max) AUC_(inf) AUC_(last) Phase Subject(uM) (hr) (hr*uM) (hr*uM) 1 D1001 3.37 1.00 22.8 21.3 D1002 3.91 2.0034.9 31.6 D1003 9.28 2.00 170 102 D1004 5.01 3.00 44.4 41.1 D1005 4.592.00 51.9 45.1 Mean 5.23 2.00 64.9 48.3 SD 2.35 0.707 60.0 31.6 2 D10012.90 2.00 40.9 33.8 D1002 1.50 1.00 14.4 13.0 D1003 2.86 0.500 25.4 23.0D1004 1.24 3.00 15.0 13.4 D1005 3.56 24.0 57.5 35.1 Mean 2.41 6.10 30.723.7 SD 0.995 10.1 18.5 10.7

TABLE 17 Results from Table 16 without D1003 of Phase 1 and D1005 ofPhase 2 C_(max) T_(max) AUC_(inf) AUC_(last) Phase Subject (uM) (hr)(hr*uM) (hr*uM) 1 D1001 3.37 1.00 22.8 21.3 D1002 3.91 2.00 34.9 31.6D1003 — — — — D1004 5.01 3.00 44.4 41.1 D1005 4.59 2.00 51.9 45.1 Mean4.22 2.00 38.5 34.8 SD  0.726  0.816 12.6 10.6 2 D1001 2.90 2.00 40.933.8 D1002 1.50 1.00 14.4 13.0 D1003 2.86  0.500 25.4 23.0 D1004 1.243.00 15.0 13.4 D1005 — — — — Mean 2.13 1.63 23.9 20.8 SD  0.878 1.1112.4  9.82

TABLE 18 Time-Concentration Results for Phase 1 and Phase 2 studies TimeMean Phase (hr) D1001 D1002 D1003 D1004 D1005 (uM) SD 1 0 0 0 0.00 0.000 0 0 0.25 0.388 0.023 0.0227 0 0 0.09 0.169 0.5 1.96 1.68 1.47 0.9310.534 1.32 0.576 1 3.37 3.47 6.11 1.62 2.93 3.5 1.63 2 2.57 3.91 9.284.77 4.59 5.02 2.53 3 2.54 3.32 6.8 5.01 4.53 4.44 1.64 6 1.28 1.7 5.252.8 2.27 2.66 1.56 9 0.715 1.39 4.51 1.9 1.45 1.99 1.47 24 0.168 0.3172.6 0.367 1.29 0.95 1.02 2 0 0 0 0 0 0 0 0 0.25 0.478 0 2.42 0.363 0.6680.786 0.946 0.5 1.88 0.483 2.86 0.683 1.04 1.39 0.98 1 2.15 1.5 2.690.802 1.11 1.65 0.77 2 2.9 1.4 2.29 1.14 0.979 1.74 0.822 3 2.78 1.12.02 1.24 0.824 1.59 0.799 6 1.7 0.824 1.33 0.77 0.597 1.04 0.457 9 1.030.588 0.922 0.71 0.296 0.71 0.29 24 1.17 0.146 0.251 0.155 3.56 1.061.47

TABLE 19 Time-Concentration Results for Phase 1 and Phase 2 studieswithout D1003 of Phase 1 and D1005 of Phase 2 Time Mean Phase (hr) D1001D1002 D1003 D1004 D1005 (uM) SD 1 0 0 0 — 0.00 0 0.00 0.00 0.25 0.3880.023 — 0 0 0.103 0.190 0.5 1.96 1.68 — 0.931 0.534 1.28 0.658 1 3.373.47 — 1.62 2.93 2.85 0.851 2 2.57 3.91 — 4.77 4.59 3.96 0.998 3 2.543.32 — 5.01 4.53 3.85 1.13 6 1.28 1.7 — 2.8 2.27 2.01 0.663 9 0.715 1.39— 1.9 1.45 1.36 0.489 24 0.168 0.317 — 0.367 1.29 0.536 0.510 2 0 0 0 00 — 0.00 0.00 0.25 0.478 0 2.42 0.363 — 0.815 1.09 0.5 1.88 0.483 2.860.683 — 1.48 1.11 1 2.15 1.50 2.69 0.802 — 1.79 0.816 2 2.9 1.40 2.291.14 — 1.93 0.811 3 2.78 1.10 2.02 1.24 — 1.79 0.777 6 1.7 0.824 1.330.77 — 1.16 0.442 9 1.03 0.588 0.922 0.71 — 0.813 0.200 24 1.17 0.1460.251 0.155 — 0.431 0.495

Example 8: PK Evaluation of Compound (I) Free Base in Combination withFumaric Acid in Humans

Example 8 involved a human clinical trial to investigate the PK profileof tablets comprising compound (I) free base and fumaric acid versus thePK profile of powder-in-capsule (“PIC”) containing compound (I) freebase in the absence of fumaric acid and excipients.

In a first study, the PK study design was a single center, randomized,open-label, two-part study. Both Part 1 and Part 2 used a 2-waycrossover methodology, with one fixed sequence and three period designedto investigate the effect of formulation, food and rabeprazole on the PKof comparative compound (I) free base formulated in capsules withoutfumaric acid and formulated in tablets in combination with fumaric acidin healthy male and female (of non-childbearing potential) subjects(N=32). Rabeprazole is an orally administered proton pump inhibitor thatinhibits the release of gastric acid. Part 1 and Part 2 methodology aresummarized in Table 20 below:

TABLE 20 Study Part Treat. Seq. Period 1 Period 2 Period 3 1 1 TreatmentA Treatment B Treatment C 1 2 Treatment B Treatment A Treatment C 2 3Treatment D Treatment E Treatment F 2 4 Treatment E Treatment DTreatment F

The treatment regimens are summarized as follows. Treatment A:Comparative powder-in-capsule formulation comprising 200 mg API underfasting conditions. Treatment B: Tablet formulation comprising 200 mgAPI under fasting conditions. Treatment C: Tablet formulation comprising200 mg API under fasting conditions in combination with 20 mgrabeprazole twice daily. Treatment D: Tablet formulation comprising 200mg API under fasting conditions. Treatment E: Tablet formulationcomprising 200 mg API under fed conditions. Treatment F: Tabletformulation comprising 200 mg API under fed conditions in combinationwith 20 mg rabeprazole twice daily. The fed meal was a typical mealcomprising moderate protein, carbohydrate and fat. Samples for PKanalysis were collected at Day 1, 0 hour (pre-dose), and at 0.5, 1, 2,3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post dose.

Among other PK effects, the study was designed to detect a two-folddifference in PK exposures between treatments following single-doseadministration. The study was further designed to measure the effect ofa typical meal (E Treatment) on fasted compound (I) free base tablet (DTreatment) PK parameters (e.g. AUC_(0-∞), C_(max), T_(max), apparent t½)by fed versus fasted comparison of pharmacokinetic parameters after asingle oral dose. The study was yet further designed to measure PPI(rabeprazole) effect on fasted compound (I) free base tablet PKparameters (C Treatment) (e.g AUC_(0-∞), C_(max), T_(max), apparentt_(1/2)) vs fasted tablet (B Treatment). The study was further designedto measure PPI (rabeprazole) effect on fed compound (I) free base tabletPK parameters (F Treatment) (e.g., AUC_(0-∞), C_(max), T_(max), apparentt_(1/2)) vs fasted tablet (D Treatment).

The comparative capsules were powder-in-capsule formulations containing50 mg compound (I) free base without fumaric acid and using a size 0light blue opaque gelatin capsule shell.

The tablets comprised the components detailed in Table 21. The tabletswere prepared as follows: The intra-granular components were blended.The intra-granular blend was slugged using a Carver press and thenmilled by mortar and pestle to form compound (I) free baseintra-granules. The intra-granules were then blended with theextra-granular components to form a tablet blend. The tablet blend wascompressed to form tablets using a Carver press.

TABLE 21 Compound (I) Free Base Tablets Amount Component Description perTablet Intra-granular Blend Compound (I) Free base API 50.00 mg  FumaricAcid Powder Special, Pharma 50.00 mg  Grade Lactose Monohydrate FastFlow 316 33.30 mg  Microcrystalline Cellulose Avicel PH-101 181.65 mg Magnesium Stearate Hyqual 1.67 mg Croscarmellose Sodium SD-711 Ac-Di-Sol5.00 mg Silica Colloidal Anhydrous Aerosil 200 1.67 mg Extra-granularBlend Magnesium Stearate Hyqual 3.33 mg Croscarmellose Sodium SD-711Ac-Di-Sol 5.00 mg Silica Colloidal Anhydrous Aerosil 200 1.67 mg Totalper tablet 333.29 mg 

The Study 1 PK Results are presented in Table 22 and the Study 2 PKresults are presented in Table 23 wherein T_(1/2) and T_(max) arereported in hours, C_(max) and C₁₂ are reported in ng/mL, AUC isreported in hr*ng/mL, “SD” refers to standard deviation, “CV” refers tothe coefficient of variation, “Geo. Mean” refers to geometric mean, “CI95% Lower” refers to the confidence interval based on the lowergeometric mean, and “CI 95% Upper” refers to the confidence intervalbased on the upper geometric mean.

TABLE 22 Study 2 PK Results T_(1/2) T_(max) C_(max) C₁₂ AUC₀₋₁₂ AUC₀₋₂₄AUC_(last) AUC_(∞) Capsule N 16 16 16 16 16 16 16 16 Mean 12.65 1.28 33935 1308 1554 1700 1722 SD 7.22 0.36 237 24 799 956 1011 1008 Min 5.560.5 68 10 331 425 605 639 Median 9.2 1.5 282 26 1100 1315 1416 1434 Max29.96 2 847 83 2736 3321 3622 3630 CV % 57.1 28.4 70 70 61 62 60 59 Geo.Mean 11.08 1.23 267 28 1074 1281 1433 1463 CI 95% Lower 8.41 1.03 180 19751 901 1037 1067 CI 95% Upper 14.59 1.46 395 40 1537 1820 1982 2007Tablet N 15 15 15 15 15 15 15 15 Mean 8.7 1.2 589 □9 2139 2485 2469 2665SD 3.66 0.65 283 24 868 1035 1116 1117 Min 5.65 0.5 325 25 1227 15001607 1612 Median 7.12 1 532 36 1734 1977 2074 2087 Max 19.38 3 1180 983804 4505 4940 4963 CV % 42 54.1 48 49 41 42 42 42 Geo. Mean 8.17 1.06535 45 1994 2310 2462 2479 CI 95% Lower 6.75 0.8 418 35 1617 1867 19902007 CI 95% Upper 9.89 1.41 684 57 2459 2858 3045 3063 Tablet + PPI N 1515 15 15 15 15 15 15 Mean 14.67 1.47 294 39 1349 1654 1917 1957 SD 4.70.79 100 16 455 558 630 648 Min 7.14 0.5 159 18 698 874 1078 1092 Median12.8 1 257 41 1282 1597 1885 1895 Max 24.22 3 476 63 2133 2513 3057 3227CV % 32 53.9 34 41 34 34 34 33 Geo. Mean 14 1.28 279 36 1277 1564 18181856 CI 95% Lower 11.75 0.94 233 28 1052 1285 1505 1536 CI 95% Upper16.68 1.74 335 46 1549 1902 2197 2243

TABLE 23 Study 1 PK Results T_(1/2) T_(max) C_(max) C₁₂ AUC₀₋₁₂ AUC₀₋₂₄AUC_(last) AUC_(∞) Capsule N 16 16 16 16 16 16 16 16 Mean 10 1.09 568 512104 2473 2690 2699 SD 3 0.46 228 16 581 692 773 777 Min 6 0.5 288 321363 1589 1705 1715 Median 10 1 472 49 1945 2287 2587 2608 Max 18 2 96585 3276 3874 4187 4199 CV % 34 41.6 40 31 28 28 29 29 Geo. Mean 10 1.01527 49 2036 2390 2594 2603 CI 95% Lower 8 0.8 426 41 1771 2075 2242 2249CI 95% Upper 12 1.26 652 57 2339 2753 3002 3013 Tablet N 16 16 16 16 1616 16 16 Mean 10 2.03 461 60 2202 2626 2848 2858 SD 3 0.94 110 15 335451 544 553 Min 6 0.5 348 38 1809 2035 2115 2112 Median 11 2 425 63 21602585 2834 2847 Max 16 4 709 96 2979 3749 4184 4209 CV % 30 46.2 24 26 1517 19 19 Geo. Mean 10 1.83 450 59 2180 2593 2803 2812 CI 95% Lower 8 1.4400 51 2018 2378 2545 2550 CI 95% Upper 11 2.38 506 67 2356 2828 30873101 Tablet + PPI N 15 15 15 15 15 15 15 15 Mean 14 2.9 139 38 923 12451561 1598 SD 5 1.38 31 8 180 259 454 490 Min 7 0.5 84 24 607 782 901 906Median 12 3 142 41 925 1279 1457 1485 Max 26 4 186 51 1144 1674 26882861 CV % 37 47.5 22 22 20 21 29 31 Geo. Mean 13 2.33 136 37 905 12181503 1535 CI 95% Lower 11 1.48 120 33 806 1076 1284 1305 CI 95% Upper 163.68 155 43 1017 1379 1759 1804

Plasma concentration C_(max) (ng/mL) linear scale results for Tablets(fasted), Tablets (Fed) and Tablets (Fed+PPI) are presented in FIG. 19A.Plasma AUC_(inf)(hr*mg/mL) linear scale results for Tablets (fasted),Tablets (Fed) and Tablets (Fed+PPI) are presented in FIG. 19B. Plasmaconcentration C_(max) (ng/mL) linear scale results for Capsules(fasted), Tablets (fasted) and Tablets (fasted+PPI) are presented inFIG. 20A. Plasma AUC_(inf)(hr*mg/mL) linear scale results for Capsules(fasted), Tablets (fasted) and Tablets (fasted+PPI) are presented inFIG. 20B.

In second—comparative—study, a single dose food and PPI PK assessmentwas done for PIC dosage form compositions containing only 100 mgcompound (I) free base (i.e., in the absence of fumaric acid andexcipients). The protocol is detailed Table 24 below wherein each panelcontained 10 human subjects.

TABLE 24 Compound (I) Panel PPI Food/Fast PIC Dose J None Fasted Day 1100 mg Day 1 K None High Fat Breakfast 100 mg Day 1 Day 1 L Rabeprazole(20 mg Fasted Day 1 100 mg Day 1 BID at −3 to day 1) M Rabeprazole (20mg High Fat Breakfast 100 mg Day 1 BID at −3 to day 1) Day 1

The results for plasma C_(max) (μM), plasma AUC_(Inf) (hr*μM), plasmaAUC₀₋₂₄ (hr*μM), plasma HL-Lambda-z (hr), plasma T_(max) (hr) and plasmaAUC_(last) (hr*μM) are presented in Table 25 below.

TABLE 25 Panel C_(max) AUC_(Inf) AUC₀₋₂₄ Lambda_z T_(max) AUC_(last) J N10 10 10 10 10 10 Mean 0.218 1.07 0.967 16 1.5 1.06 SD 0.153 0.635 0.6087.6 0.236 0.633 Min 0.043 0.31 0.23 7.3 1 0.31 Median 0.2 1.1 0.98 131.5 1 Max 0.46 2 1.9 29 2 2 CV % 69.93 59.16 62.82 47.44 15.71 59.98 K N10 10 10 10 10 10 Mean 0.235 1.7 1.56 9.82 4 1.69 SD 0.0839 0.641 0.592.85 0.816 0.644 Min 0.054 0.72 0.58 5 3 0.72 Median 0.25 1.6 1.5 9.7 41.6 Max 0.36 2.8 2.6 16 6 2.8 CV % 35.71 37.69 37.91 29.05 20.41 38.06 LN 10 10 10 10 10 10 Mean 0.0116 0.274 0.157 12.8 5.7 0.261 SD 0.00390.0599 0.0365 4.91 6.45 0.0489 Min 0.0056 0.2 0.09 7.6 3 0.2 Median0.012 0.27 0.16 11 4 0.27 Max 0.019 0.41 0.22 21 24 0.35 CV % 33.3 21.8223.2 38.4 113.11 18.71 M N 10 10 10 10 10 10 Mean 0.0406 0.657 0.47113.4 6.9 0.642 SD 0.0112 0.188 0.118 5.85 2.51 0.188 Min 0.026 0.3 0.257.5 3 0.3 Median 0.04 0.67 0.52 12 7 0.66 Max 0.062 0.87 0.57 26 12 0.85CV % 27.64 28.68 25.03 43.63 36.44 29.34

The ratios of PK parameters by panels J to M are presented in Table 26below where “J” refers to Panel J (Fast), “K” refers to Panel K (Fed),“L” refers to Panel L (Fast+Rabeprazole PPI), and “M” refers to Panel M(Fed+Rabeprazole PPI).

TABLE 26 Parameter N J K L M K/J L/J M/J M/L AUC_(inf) 10 1.073 1.7010.274 0.657 1.585 0.256 0.612 2.395 C_(max) 10 0.218 0.235 0.012 0.0411.076 0.053 0.186 3.487

The comparative results for the mean concentration (μM) for panels J toM versus time (hr) are presented in FIG. 21A (linear scale) and 21B (logscale). Plasma concentration (μM) comparative results for individuals inpanel J versus time (hr) are presented in FIG. 22A (linear scale) and22B (log scale). Plasma concentration (μM) comparative results forindividuals in panel K versus time (hr) are presented in FIG. 23A(linear scale) and 23B (log scale). Plasma concentration (μM)comparative results for individuals in panel L versus time (hr) arepresented in FIG. 24A (linear scale) and 24B (log scale). Plasmaconcentration (μM) comparative results for individuals in panel M versustime (hr) are presented in FIG. 25A (linear scale) and 25B (log scale).Plasma concentration comparative C_(max) (μM) linear scale results forPanel J (Fast), Panel K (Fed), Panel L (Fast+Rabeprazole PPI) and PanelM (Fed+Rabeprazole PPI) are presented in FIG. 26A. Plasma comparativeAUC_(inf)(hr*μM) linear scale results for Panel J, Panel K, Panel L andPanel M are presented in FIG. 26B.

The second (comparative) Example 8 study results for PIC compound (I)free base dosed in the absence of fumaric acid indicate high variabilityin fasting subjects and a large decrease in compound (I) exposure when aPPI is taken. In contrast, the combination of compound (I) free base andfumaric acid from the first Example 8 study showed reduced variabilityin fasting subjects and maintenance of therapeutic compound (I) exposurewhen a PPI is taken.

Example 9: Preparation of Tablets Comprising Compound (I) Free Base andFumaric Acid

The tablets comprised the components detailed in Table 27. The tabletswere prepared as follows: The intra-granular components were blended.The intra-granular blend was slugged using a Carver press and thenmilled by mortar and pestle to form compound (I) free baseintra-granules. The intra-granules were then blended with theextra-granular components to form a tablet blend. The tablet blend wascompressed to form tablets using a Carver press.

TABLE 27 Tablet 1 Tablet 2 mg/ mg/ Component Description wt. % tabletwt. % tablet Intra-granular Compound (I) Free API 20.0 200.0 25.0 200.0Base Lactose monohydrate Fast Flo 316 10.0 100.0 10.0 80.0Microcrystalline Avicel PH-102 45.5 455.0 35.5 284.0 celluloseCroscarmellose Ac-Di-Sol 1.5 15.0 1.5 12.0 sodium Magnesium stearateHyqual 2257 0.5 5.0 0.5 4.0 Extra-granular Fumaric acid Powder Special,20.0 200.0 25.0 200.0 Pharma Grade Croscarmellose Ac-Di-Sol 1.5 15.0 1.512.0 sodium Magnesium stearate Hyqual 2257 1.0 10.0 1.0 10.0 Tablet CoreTotal 100.0 1000.0 100.0 800.0

Example 10: Preparation of Compound (I) Amorphous and CrystallineChloride Salts

The amorphous chloride salt of compound (I) was prepared as follows.Concentrated HCl (370%) was diluted to 0.2 M with dichloromethane(“DCM”). About 200 mg of compound (I) free base Type A was added to a 20mL glass vial to which 1.5 mL DCM was added to generate a clearsolution. Sufficient HCl/DCM solution (1.52 mL) was added drop wise toprovide a molar ratio of compound (I) free base to HCl of 1:1.1. About 2mg of compound (I) chloride salt type A polymorph seed crystal was addedto the vial as seed whereupon 1 mL of ethyl acetate was added therebyresulting in an admixture having a cloudy appearance. The admixture wasstirred at room temperature for 1 day and the solids were then isolatedby centrifugation and dried at room temperature. The solids werecollected and analyzed by ITPLC for purity and by XRPD. Purity by ITPLCwas determined to be 99.8% and having a stoichiometry of 1. The XRPDresults for the amorphous chloride salt and the crystalline chloridetype A salt are depicted in FIG. 27 as compared to a compound (I)crystalline chloride type A salt reference.

In a first evaluation for preparing compound (I) chloride salt type Apolymorph, concentrated HCl (37%) was diluted to 0.2 M withtetrahydrofuran (“THF”). 100 mg of compound (I) free base Type A wasadded to a 20 mL glass vial to which 1.5 mL of THF/H₂O (19:1, v/v) wasadded to generate a clear solution. Dilute HCl was added to the freebase solution in increments of 170 μL until the stoichiometric ratio ofcompound (I) to HCl reached 1.1. About 8 mg of compound (I) chloridesalt type A polymorph seed crystal thereby resulting in an admixture.The admixture was stirred at room temperature for 1 day and the solidswere then isolated by centrifugation and dried at room temperature. Thesolids were collected and analyzed by HPLC for purity and by XRPD.Purity by HPLC was determined to be 99.41% and having a stoichiometryof 1. In a second evaluation for preparing compound (I) chloride salttype A polymorph, concentrated HCl (37%) was diluted to 0.2 M withTHF/H₂O (19:1, v/v). About 500 mg of compound (I) free base was added toa 20 mL glass vial to which 7.5 mL of THF/H₂O (19:1, v/v) was added togenerate a clear solution. A total of 4.1 mL of the 0.2 M HCl was addedto the free base solution drop-wise until the stoichiometric ratio ofcompound (I) to HCl reached 1.1. About 8 mg of compound (I) chloridesalt type A polymorph seed crystal thereby resulting in an admixture.The admixture was stirred at room temperature for 18 hours and thesolids were then isolated by centrifugation and dried at roomtemperature. The solids were collected and analyzed by HPLC for purityand by XRPD. Purity by HPLC was determined to be 99.74% and having astoichiometry of 1. The XRPD results for the 100 mg and 500 mg scalecompound (I) crystalline chloride type A salt preparations as comparedto compound (I) crystalline chloride type A salt reference are depictedin FIG. 28.

In a third evaluation for preparing compound (I) chloride salt type Apolymorph, about 20 mg compound (I) free base Type A was combined with0.5 mL ACN in a glass vial. About 0.17 mL of 0.2 M HCl in ethanol wasadded in a molar charge ratio of free base to acid of 1:1.1. About 2 mgcompound (I) chloride salt Type A was seed added to the vial to form anadmixture. The admixture was stirred at 5° C. for about 2 days. Thesolids were then isolated by centrifugation and dried at roomtemperature. The solids were collected and analyzed by HPLC for purityand by XRPD. Purity by HPLC was determined to be 99.04% and have astoichiometry of 1. The XPRD results are presented in FIG. 29. XRPD peakdata for the compound (I) chloride salt type A polymorph is recited inTable 28.

TABLE 28 Compound (I) chloride salt type A polymorph XRPD data Pos.Height FWHM Left d-spacing Rel. Int. [° 2Th.] [cts] [° 2Th.] [Å] [%]3.973 791.424 0.0895 22.240 95.67 6.831 827.242 0.1023 12.94 100.007.917 387.033 0.1023 11.167 46.79 10.458 376.445 0.1151 8.459 45.5111.865 313.483 0.1023 7.459 37.89 14.209 214.622 0.1023 6.234 25.9415.793 798.100 0.1151 5.611 96.48 17.018 82.976 0.5117 5.21 10.03 18.09695.793 0.154 4.902 11.58 19.758 161.731 0.1279 4.493 19.55 20.891 49.50.2047 4.252 5.98 22.0313 51.738 0.307 4.035 6.25 25.225 59.497 0.3073.531 7.19

Example 11: Preparation of Compound (I) Crystalline Sulfate Salts

Compound (I) sulfate salt type A polymorph was prepared according to thefollowing method. About 0.9 g of compound (I) free base Type A wascombined with 4.6 mL DCM in a 10 mL crystallizer followed by stirring atabout 20° C. to obtain a clear solution. 7.44 mL of 0.2 M H2SO4 wasadded stepwise over 0.5 hours with stirring. The contents weretransferred to a second 100 mL crystallizer to remove gel-like material.The solution was heated to 35° C. followed by addition of 5.5 mL ACN.100 mg of compound (I) sulfate salt type A seed was added to form acloudy admixture. The admixture was stirred at 35° C. for 0.5 hours and60 mL of ACN was added over 12 hours. Thereafter, the admixture wascooled to 20° C. over 2 hours and then stirred at 20° C. for 3 hours.The crystals were isolated by filtration and washed with 2 mL ACN. Thewet crystals were dried at 45° C. under vacuum for 4 hours. The solidswere collected providing 1.1 g with a yield of about 87.9%. The crystalswere characterized by XRPD (FIG. 30), TGA/DSC, ¹H NMR and HPLC. TGAresults indicated a weight loss of 9.1% up to 100° C. DSC resultsindicated three endotherms at 138.0° C., 216.8° C. and 272.0° C. (peaktemperature). ¹H NMR results indicated 5.80 ACN residual in compound (I)sulfate type A. ITPLC results indicated 99.48% purity.

Stoichiometry of sulfate formation was evaluated wherein two batches ofcompound (I) sulfate type A were prepared as described elsewhere hereinand at molar ratios of compound (I) free base to sulfate anion of 0.49:1and 0.81:1. Unreacted free base type A was observed from the batchprepared at the mole ratio of 0.49:1 suggesting that compound (I)sulfate type A is more likely to be a mono-sulfate salt. The XRPDresults are presented in FIG. 31. XRPD peak data for the compound (I)sulfate salt type A polymorph is recited in Table 29.

TABLE 29 Compound (I) sulfate salt type A polymorph XRPD data Pos.Height FWHM Left d-spacing Rel. Int. [° 2Th.] [cts] [° 2Th.] [Å] [%]3.722 442.219 0.1151 23.741 52.28 5.17 366.646 0.1791 17.094 43.34 7.28332.047 0.1535 12.143 39.25 8.115 353.807 0.1535 10.895 41.83 10.336591.699 0.1535 8.559 69.95 11.525 628.358 0.2303 7.678 74.28 13.121347.351 0.2047 6.748 41.06 13.755 425.278 0.1023 6.438 50.28 14.712433.923 0.179 6.021 51.3 15.057 457.369 0.1791 5.884 54.07 16.294845.897 0.1663 5.44 100 16.955 204.818 0.4093 5.229 24.21 18.282 429.4180.307 4.853 50.76 19.736 406.63 0.307 4.498 48.07 20.596 211.892 0.25584.313 25.05 21.272 174.449 0.2047 4.177 20.62 22.356 246.142 0.40933.977 29.1 23.215 149.993 0.4093 3.832 17.73 24.935 118.488 0.2558 3.57114.01 25.943 171.613 0.358 3.435 20.29 26.52 161.794 0.307 3.361 19.1327.967 93.482 0.307 3.19 11.05 31.514 21.405 0.614 2.839 2.53

When introducing elements of the present disclosure or the preferredembodiments(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

This written description uses examples to disclose the invention,including the best mode, and also to enable any person skilled in theart to practice the invention, including making and using any devices orsystems and performing any incorporated methods. The patentable scope ofthe invention is defined by the claims, and may include other examplesthat occur to those skilled in the art. Such other examples are intendedto be within the scope of the claims if they have structural elementsthat do not differ from the literal language of the claims, or if theyinclude equivalent structural elements with insubstantial differencesfrom the literal languages of the claims.

What is claimed is:
 1. A salt composition comprising: (1) a cationformed from a free base of structure (I):

 and (2) an anion selected from mesylate, chloride and sulfate.
 2. Thecomposition of claim 1 wherein the salt is crystalline.
 3. Thecomposition of claim 2 wherein the salt is the mesylate salt.
 4. Thecomposition of claim 3 wherein the mesylate salt is a type A polymorphhaving an XRPD pattern comprising at least three characteristic peaksselected from peaks with 2θ angle degrees±0.2 2θ angle degrees of about3.78, about 6.48, about 7.91, about 9.92, about 11.89, about 14.26,about 15.12, about 15.89, about 17.24, about 18.10, about 19.86, about20.55 and about 21.41.
 5. The composition of claim 3 wherein at least 50percent by weight of the mesylate salt dissolves in a pH 4.5 aqueousmedium at 37° C. in 10 minutes and wherein at least 80 percent by weightof the mesylate salt dissolves in the pH 4.5 aqueous medium at 37° C. in30 minutes.
 6. The composition of claim 2 wherein the salt is thechloride salt.
 7. The composition of claim 6 wherein chloride salt is atype A polymorph having an XRPD pattern comprising at least threecharacteristic peaks selected from peaks with 2θ angle degrees±0.2 2θangle degrees of about 3.97, about 6.83, about 7.92, about 10.46, about11.87, about 14.21, about 15.79 and about 19.76.
 8. The composition ofclaim 2 wherein the salt is the sulfate salt.
 9. The composition ofclaim 8 wherein sulfate salt is a type A polymorph having an XRPDpattern comprising at least three characteristic peaks selected fromselected from peaks with 2θ angle degrees±0.2 2θ angle degrees of about3.72, about 5.17, about 10.34, about 11.53, about 13.76, about 14.71,about 15.06, about 16.29, about 18.28 and about 19.74.